Uridine diphosphate derivatives, compositions and methods for treating neurodegenerative disorders

ABSTRACT

This disclosure relates to uridine diphosphate (UDP) derivatives, compositions comprising therapeutically effective amounts of those UDP derivatives and methods of using those derivatives or compositions in treating disorders that are responsive to ligands, such as agonists, of P 2 Y 6  receptor, e.g., neuronal disorders, including neurodegenerative disorders (e.g., Alzheimer&#39;s disease) and traumatic CNS injury, as well as pain.

RELATED APPLICATIONS

This application is a continuation of and claims priority to PCTapplication PCT/US2012/58080, filed Sep. 28, 2012, which claims thebenefit of U.S. Provisional Patent Application 61/541,919, filed Sep.30, 2011. Each of the foregoing applications is incorporated herein byreference in their entirety.

FIELD OF THE INVENTION

This disclosure relates to compounds, compositions and methods fortreating neurodegeneration, pain and traumatic brain injury that areresponsive to the P₂Y₆ receptor.

BACKGROUND OF THE INVENTION

P₂Y receptors are G-protein-coupled receptors (GPCRs) that areselectively activated by naturally occurring extracellular nucleotides,including, for example, adenine and pyrimidine nucleotides. There aretwo clusters of P₂Y receptors: the G_(q)-coupled P₂Y₁-like receptors,including P₂Y_(1,2,4,6,11) subtypes; and the G_(i)-coupled P₂Y₁₂-likereceptors, including P₂Y_(12, 13, 14) subtypes. Of the four P₂Y₆receptors, i.e., P₂Y_(2, 4, 6, 14) subtypes, which can be activated bypyrimidine nucleotides, the P₂Y₂ and P₂Y₄ subtypes are activated byuridine triphosphate (UTP), P₂Y₆ is activated by uridine diphosphate(UDP), and P₂Y₁₄ is activated by UDP or UDP-glucose.

The P₂Y₆ receptor has been implicated in a number of disorders,including, for example, neurodegeneration, osteoporosis, ischemic effectin skeletal muscle, and diabetes. It has been reported that agonists ofP₂Y₆ receptor counteract apoptosis induced by tumor necrosis factor α inastrocytoma cells and induce protection in a model of ischemic hindlegskeletal muscle. P₂Y₆ receptor was also reported to play a role inphagocytosis in microglial cells when activated by its endogenousagonist UDP. See, e.g., Malmsjo et al. BMC Pharmacol. 2003, 3, 4;Balasubramanian et al. Biochem. Pharmacol. 2010, 79, 1317-1332; Kim etal. Cell. Mol. Neurobiol. 2003, 23, 401-418; Mamedova et al. Pharmacol.Res. 2008, 58, 232-239; Korcok et al. J. Biol. Chem. 2005, 58, 232-239;and Koizumi et al. Nature, 2007, 446, 1091-1095. These reports suggestthat ligands of the P₂Y₆ receptor are of interest in the search for newtreatments for P₂Y₆ receptor-related conditions.

Therefore, there is a need for new ligands, such as agonists, of theP₂Y₆ receptor that are useful in therapeutic preparations for thetreatment of disorders responsive to the receptor, includingneurodegeneration, traumatic brain injury and pain.

SUMMARY OF THE INVENTION

The present disclosure addresses the aforementioned need by providingcompounds of formulae I and II:

wherein the variables are as defined herein, along with pharmaceuticallyacceptable salts thereof. These compounds are typically selectiveligands of the P₂Y₆ receptor. In certain embodiments, the compounds asdescribed herein are agonists of the P₂Y₆ receptor, which activate theP₂Y₆ receptor. Compounds of formulae I and II can be used to treat theconditions as described herein.

The present disclosure also provides compositions that comprise theabove compounds or a pharmaceutically acceptable salt thereof. Thedisclosure also includes the use of the compounds disclosed herein inthe manufacture of a medicament for the treatment of one or more of theconditions described herein.

In another aspect of the disclosure, there is provided a method fortreating neurodegeneration, pain and traumatic brain injury in a subjectin need or at risk thereof using a compound described herein.

In another aspect, the disclosure provides methods for decreasing plaqueburden, improving cognitive function, decreasing or delaying cognitiveimpairment, improving or restoring memory, enhancing synapticplasticity, or improving hippocampal long term potentiation byadministering to a subject in need or at risk thereof a P₂Y₆ agonist.Also provided are methods of enhancing beta amyloid clearance. Subjectsin need include subjects having Alzheimer's disease (including subjectssuspected of having Alzheimer's disease). Additional subjects in needthereof are subjects having Down Syndrome, and administration of a P₂Y₆agonist is used to treat Down Syndrome by, for example, improvingcognitive function, decreasing cognitive impairment, improving orrestoring memory, improving hippocampal long term potentiation,enhancing synaptic plasticity, or enhancing clearance of beta amyloid.Exemplary P₂Y₆ agonists are disclosed herein.

DETAILED DESCRIPTION OF THE FIGURES

FIG. 1 shows two-photon microscopy images of the amyloid plaques labeledwith methoxyX04 in the barrel cortex in living PSAPP mice: (A) image onday 1; (B) magnified view of the portion of the image in the white boxin FIG. 1A, in which the blood plasma was labeled with Rhodaminedextran; (C) magnified view of the portion of the image in the white boxin FIG. 1A, where the arrows indicate dense core plaques; (D) image ofthe same imaging area on day 4, after the injection of UDP; (E)magnified view of the portion of the image in the white box in FIG. 1D,in which the blood plasma was labeled with Rhodamine dextran; and (F)magnified view of the portion of the image in the white box in FIG. 1D,where the arrows indicate dense core plaques.

FIG. 2 shows a quantitative analysis of the number of plaques, plaqueload and size of cross-section of individual plaques in the barrelcortex in PSAPP mice after treatment with UDP or artificial cerebralspinal fluid (ACSF): (A) quantitative analysis of the number of plaques;(B) quantitative analysis of the plaque load; (C) quantitative analysisof the size of cross-section of plaques; (D) UDP treatment reducesplaque load as shown by significant reductions in day 4/day 1 ratios ofplaque load; and (E) UDP treatment reduces number of plaques as shown bysignificant reductions in day 4/day 1 ratios of plaque load.

FIG. 3 shows postmortem immunohistochemistry analysis of the plaque loadin cortex and hippocampus of PSAPP mice after treatment with UDP.Amyloid beta peptide specific antibodies β1-40 and β1-42 were used inthe immunohistochemistry analysis: (A) immunohistochemistry analysisusing β1-40 on day 1; (B) immunohistochemistry analysis using β1-40 onday 4, after treatment with UDP; (C) immunohistochemistry analysis usingβ1-42 on day 1; and (D) immunohistochemistry analysis using β1-42 on day4, after treatment with UDP.

FIG. 4 shows quantification of plaque load (%) in the cortex andhippocampus of the PSAPP mice after treatment with UDP or ACSF. Amyloidbeta peptide specific antibodies β1-40 and β1-42 were used in thequantification. (A) plaque load (%) in cortex using β1-40 staining; (B)plaque load (%) in hippocampus using β1-40 staining; (C) plaque load (%)in cortex using β1-42 staining; (D) plaque load (%) in hippocampus usingβ1-42 staining; (E) UDP treatment decreased soluble Aβ40 level detectedwith ELISA; and (F) UDP treatment decreased soluble Aβ42 level detectedwith ELISA.

FIG. 5 shows a postmortem immunohistochemistry analysis of the plaqueload in cortex and hippocampus of PSAPP mice after intraperitoneal(i.p.) injection of 3-phenacyl-UDP for 2, 4 and 6 consecutive days.Amyloid beta specific antibody β1-40 was used in the analysis. (A)immunohistochemistry analysis using β1-40 without 3-phenacyl-UDPtreatment; (B) immunohistochemistry analysis using β1-40 afterintraperitoneal injection of 3-phenacyl-UDP for 2 consecutive days; (C)immunohistochemistry analysis using β1-40 after intraperitonealinjection of 3-phenacyl-UDP for 4 consecutive days; and (D)immunohistochemistry analysis using β1-40 after intraperitonealinjection of 3-phenacyl-UDP for 6 consecutive days.

FIG. 6 shows quantification of plaque load (%) in cortex (Cx) andhippocampus (Hp) of the PSAPP mice after treatment with 3-phenacyl-UDPor vehicle control for 2, 4, 6 consecutive days and for 6 days+2 weeks.The vehicle controls used for intracerebroventricular (icv) andIntraperitoneal (ip) administration of compounds were ACSF and saline,respectively. Amyloid beta peptide specific antibody β1-40 was used inquantification. (A) Plaque load (%) in cortex using β1-40 staining; (B)plaque load (%) in hippocampus using β1-40 staining; (C) Aβ40 plaqueload (%) in hippocampus after one week of daily treatment with3-phenacyl-UDP (PSB0474) at three doses; (D) Aβ42 plaque load (%) inhippocampus after one week of daily treatment with 3-phenacyl-UDP(PSB0474) at three doses; (E) Aβ40 plaque load (%) in cortex after oneweek of daily treatment with 3-phenacyl-UDP (PSB0474) at three doses;and (F) Aβ42 plaque load (%) in cortex after one week of daily treatmentwith 3-phenacyl-UDP (PSB0474) at three doses.

FIG. 7 shows freezing behavior (freezing %) of PASPP mice in fearconditioning studies after treatment with ACSF or UDP: (A) freezingbehavior (freezing %) of PASPP mice 5 minutes following treatment withACSF and UDP; (B) analysis of total freezing percentage of PSAPP micetreated with ACSF or UDP; and (C) using the contextual fear conditioningtest PSAPP mice treated with ACSF (white bar) showed significantly lessfreezing time compared to the age-matched wildtype (line bar),suggesting the memory deficits in PS1/APP; UDP-treatment 3 days prior tothe test significantly improved the freezing behavior (black bar)compared to ACSF treatment.

FIG. 8 shows hippocampal long-term potentiation (LTP) recorded as fieldexcitatory postsynaptic potential (fEPSP) % in PSAPP mice, withhigh-frequency stimulation (HFS), 100 pulses at 100 Hz, four times in20-second intervals: (A) depressed LTP (fEPSP %) at the schaffercollateral synapse within the CA1 area of the hippocampus in aged PSAPPmice (PSAPP+/+), as compared to littermates (PSAPP−/−); (B) increasedLTP (fEPSP %) in PSAPP mice after treatment with UDP or ACSF; (C)analysis of the last 15 min potentiation, as fEPSP slope (%), in PSAPPmice.

FIG. 9 shows freezing behavior (as freezing %) of PASPP mice in fearconditioning studies after treatment with 3-phenacyl-UDP (PSB0474). (A)freezing behavior (freezing %) of control littermates (PSAPP−/−), andPASPP mice 5 minutes following treatment with saline vehicle control orwith 3-phenacyl-UDP (PSB0474) at two different dosages, i.e. 1 μg/ml and1 mg/ml; (B) analysis of total freezing percentage of PSAPP mice; and(C) using the contextual fear conditioning test PSAPP mice treated withACSF (white bar) showed significantly less freezing time compared to theage-matched wildtype (line bar), demonstrating the memory deficits inPS1/APP; one week treatment with 1 ug/kg 3-phenacyl-UDP (PSB0474) (greybar) rescued the memory deficit as compared to the vehicle treatment(white bar).

FIG. 10 shows dose-response activation of the P₂Y₆ receptor usingcompounds of the present disclosure, where compounds were tested foractivation of P₂Y₆ receptor by measuring receptor induced Ca²⁺ changeswith the fluorescent Ca²⁺ indicator fluo-4: (A) dose-response activationof the P₂Y₆ receptor using the sodium salt of compound 6; (B)dose-response activation of the P₂Y₆ receptor using the sodium salt ofcompound 3; (C) dose-response activation of the P₂Y₆ receptor using thesodium salt of compound 4; (D) dose-response activation of the P₂Y₆receptor using the sodium salt of compound 1; (E) dose-responseactivation of the P₂Y₆ receptor using the sodium salt of compound 5; (F)dose-response activation of the P₂Y₆ receptor using the sodium salt ofcompound 44; (G) dose-response activation of the P₂Y₆ receptor using thesodium salt of compound 45; (H) dose-response activation of the P₂Y₆receptor using the sodium salt of compound 46; (1) dose-responseactivation of the P₂Y₆ receptor using the sodium salt of compound 47;(J) dose-response activation of the P₂Y₆ receptor using the sodium saltof compound 48; and (K) dose-response activation of the P₂Y₆ receptorusing the sodium salt of compound 49.

FIG. 11 shows freezing behavior (freezing %) of PASPP mice in fearconditioning studies after treatment with vehicle control or compound 5:using the contextual fear conditioning test PSAPP mice treated withvehicle control (black bar) showed significantly less freezing timecompared to the age-matched wildtype (white bar), suggesting the memorydeficits in PSAPP; administration of compound 5 prior to the testsignificantly improved the freezing behavior (line bar) compared to thecontrol treatment indicating that compound 5 restores memory.

FIG. 12 shows plaque load in cortex (Cx) and hippocampus (Hp) of thePSAPP mice after treatment with compound 5 or vehicle control. (A) Aβplaque load (%) in cortex after treatment with compound 5 or vehiclecontrol; (B) Aβ plaque load (%) in hippocampus after treatment withcompound 5 or vehicle control; and (C) postmortem immunohistochemistryanalysis of the Aβ42 plaque load in cortex and hippocampus of PSAPP miceafter treatment with compound 5 or vehicle control. Amyloid betaspecific antibody β1-42 was used in the analysis.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

Unless otherwise defined herein, scientific and technical terms used inthis application shall have the meanings that are commonly understood bythose of ordinary skill in the art. Generally, nomenclature used inconnection with, and techniques of, chemistry, cell and tissue culture,molecular biology, cell and cancer biology, neurobiology,neurochemistry, virology, immunology, microbiology, pharmacology,genetics and protein and nucleic acid chemistry, described herein, arethose well known and commonly used in the art.

The methods and techniques of the present disclosure are generallyperformed, unless otherwise indicated, according to conventional methodswell known in the art and as described in various general and morespecific references that are cited and discussed throughout thisspecification. See, e.g. “Principles of Neural Science”, McGraw-HillMedical, New York, N.Y. (2000); Motulsky, “Intuitive Biostatistics”,Oxford University Press, Inc. (1995); Lodish et al., “Molecular CellBiology, 4th ed.”, W. H. Freeman & Co., New York (2000); Griffiths etal., “Introduction to Genetic Analysis, 7th ed.”, W. H. Freeman & Co.,N.Y. (1999); and Gilbert et al., “Developmental Biology, 6th ed.”,Sinauer Associates, Inc., Sunderland, Mass. (2000).

Chemistry terms used herein are used according to conventional usage inthe art, as exemplified by “The McGraw-Hill Dictionary of ChemicalTerms”, Parker S., Ed., McGraw-Hill, San Francisco, C.A. (1985).

All of the above, and any other publications, patents and publishedpatent applications referred to in this application are specificallyincorporated by reference herein. In case of conflict, the presentspecification, including its specific definitions, will control.

The term “agent” is used herein to denote a chemical compound (such asan organic or inorganic compound, a mixture of chemical compounds), abiological macromolecule (such as a nucleic acid, an antibody, includingparts thereof as well as humanized, chimeric and human antibodies andmonoclonal antibodies, a protein or portion thereof, e.g., a peptide, alipid, a carbohydrate), or an extract made from biological materialssuch as bacteria, plants, fungi, or animal (particularly mammalian)cells or tissues. Agents include, for example, agents that are knownwith respect to structure, and those that are not known with respect tostructure. The P₂Y₆ binding activity (such as agonist activity) of suchagents may render them suitable as “therapeutic agents” in the methodsand compositions of this disclosure.

A “patient,” “subject,” or “individual” are used interchangeably andrefer to either a human or a non-human animal. These terms includemammals, such as humans, primates, livestock animals (including bovines,porcines, etc.), companion animals (e.g., canines, felines, etc.) androdents (e.g., mice and rats).

“Treating” a condition or patient refers to taking steps to obtainbeneficial or desired results, including clinical results. Beneficial ordesired clinical results include, but are not limited to, alleviation,amelioration, or slowing the progression, of one or more symptomsassociated with a neuronal disorder, including neurodegeneration andtraumatic brain injury, as well as pain. In certain embodiments,treatment may be prophylactic. Exemplary beneficial clinical results aredescribed herein.

“Administering” or “administration of” a substance, a compound or anagent to a subject can be carried out using one of a variety of methodsknown to those skilled in the art. For example, a compound or an agentcan be administered, intravenously, arterially, intradermally,intramuscularly, intraperitonealy, intravenously, subcutaneously,ocularly, sublingually, orally (by ingestion), intranasally (byinhalation), intraspinally, intracerebrally, and transdermally (byabsorption, e.g., through a skin duct). A compound or agent can alsoappropriately be introduced by rechargeable or biodegradable polymericdevices or other devices, e.g., patches and pumps, or formulations,which provide for the extended, slow or controlled release of thecompound or agent. Administering can also be performed, for example,once, a plurality of times, and/or over one or more extended periods. Insome aspects, the administration includes both direct administration,including self-administration. and indirect administration, includingthe act of prescribing a drug. For example, as used herein, a physicianwho instructs a patient to self-administer a drug, or to have the drugadministered by another and/or who provides a patient with aprescription for a drug is administering the drug to the patient.

Appropriate methods of administering a substance, a compound or an agentto a subject will also depend, for example, on the age of the subject,whether the subject is active or inactive at the time of administering,whether the subject is cognitively impaired at the time ofadministering, the extent of the impairment, and the chemical andbiological properties of the compound or agent (e.g. solubility,digestibility, bioavailability, stability and toxicity). In someembodiments, a compound or an agent is administered orally, e.g., to asubject by ingestion. In some embodiments, the orally administeredcompound or agent is in an extended release or slow release formulation,or administered using a device for such slow or extended release.

A “therapeutically effective amount” or a “therapeutically effectivedose” of a drug or agent is an amount of a drug or an agent that, whenadministered to a subject will have the intended therapeutic effect. Thefull therapeutic effect does not necessarily occur by administration ofone dose, and may occur only after administration of a series of doses.Thus, a therapeutically effective amount may be administered in one ormore administrations. The precise effective amount needed for a subjectwill depend upon, for example, the subject's size, health and age, thenature and extent of cognitive impairment or other symptoms of thecondition being treated, such as neurodegeneration (such as Alzheimer'sdisease), pain and traumatic brain injury, the therapeutics orcombination of therapeutics selected for administration, and the mode ofadministration. The skilled worker can readily determine the effectiveamount for a given situation by routine experimentation.

“Ligand” as used herein refers to any molecule that is capable ofspecifically binding to another molecule, such as the P₂Y₆ receptor. Theterm “ligand” includes both agonists and antagonists. “Agonist” means anagent which, when interacting, either directly or indirectly, with abiologically active molecule (e.g. an enzyme or a receptor) causes anincrease in the biological activity thereof. “Antagonist” means an agentwhich, when interacting, either directly or indirectly, with abiologically active molecule(s) (e.g. an enzyme or a receptor) causes adecrease in the biological activity thereof. In certain embodiments, thecompounds of the present disclosure are agonists of P₂Y₆ receptor.

The term “aliphatic” as used herein means a straight chained or branchedalkyl, alkenyl or alkynyl. It is understood that alkenyl or alkynylembodiments need at least two carbon atoms in the aliphatic chain.Aliphatic groups typically contains from 1 (or 2) to 12 carbons, such asfrom 1 (or 2) to 4 carbons.

The term “aryl” as used herein means a monocyclic or bicycliccarbocyclic aromatic ring system. Phenyl is an example of a monocyclicaromatic ring system. Bicyclic aromatic ring systems include systemswherein both rings are aromatic, e.g., naphthyl, and systems whereinonly one of the two rings is aromatic, e.g., tetralin.

The term “heterocyclic” as used herein means a monocyclic or bicyclicnon-aromatic ring system having 1 to 3 heteroatom or heteroatom groupsin each ring selected from O, N, NH, S, SO, or SO₂ in a chemicallystable arrangement. In a bicyclic non-aromatic ring system embodiment of“heterocyclyl”, one or both rings may contain said heteroatom orheteroatom groups. In another heterocyclic ring system embodiment, anon-aromatic heterocyclic ring may optionally be fused to an aromaticcarbocycle.

Examples of heterocyclic rings include 3-1H-benzimidazol-2-one,3-(1-alkyl)-benzimidazol-2-one, 2-tetrahydrofuranyl,3-tetrahydrofuranyl, 2-tetrahydrothiophenyl, 3-tetrahydrothiophenyl,2-morpholino, 3-morpholino, 4-morpholino, 2-thiomorpholino,3-thiomorpholino, 4-thiomorpholino, 1-pyrrolidinyl, 2-pyrrolidinyl,3-pyrrolidinyl, 1-tetrahydropiperazinyl, 2-tetrahydropiperazinyl,3-tetrahydropiperazinyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl,1-pyrazolinyl, 3-pyrazolinyl, 4-pyrazolinyl, 5-pyrazolinyl,1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl,2-thiazolidinyl, 3-thiazolidinyl, 4-thiazolidinyl, 1-imidazolidinyl,2-imidazolidinyl, 4-imidazolidinyl, 5-imidazolidinyl, indolinyl,tetrahydroquinolinyl, tetrahydroisoquinolinyl, benzothiolane,benzodithiane, and 1,3-dihydro-imidazol-2-one.

The term “heteroaryl” as used herein means a monocyclic or bicyclicaromatic ring system having 1 to 3 heteroatom or heteroatom groups ineach ring selected from O, N, NH or S in a chemically stablearrangement. In such a bicyclic aromatic ring system embodiment of“heteroaryl” both rings may be aromatic; and one or both rings maycontain said heteroatom or heteroatom groups.

Examples of heteroaryl rings include 2-furanyl, 3-furanyl, N-imidazolyl,2-imidazolyl, 4-imidazolyl, 5-imidazolyl, benzimidazolyl, 3-isoxazolyl,4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl,N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl,2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (e.g.,3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (e.g.,5-tetrazolyl), triazolyl (e.g., 2-triazolyl and 5-triazolyl), 2-thienyl,3-thienyl, benzofuryl, benzothiophenyl, indolyl (e.g., 2-indolyl),pyrazolyl (e.g., 2-pyrazolyl), isothiazolyl, 1,2,3-oxadiazolyl,1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl,1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, purinyl,pyrazinyl, 1,3,5-triazinyl, quinolinyl (e.g., 2-quinolinyl,3-quinolinyl, 4-quinolinyl), and isoquinolinyl (e.g., 1-isoquinolinyl,3-isoquinolinyl, or 4-isoquinolinyl).

The term “cycloalkyl or cycloalkenyl” refers to a monocyclic or fused orbridged bicyclic carbocyclic ring system that is not aromatic.Cycloalkenyl rings have one or more units of unsaturation. Exemplarycycloalkyl or cycloalkenyl groups include cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl,norbornyl, adamantyl and decalinyl.

As used herein, the carbon atom designations may have the indicatedinteger and any intervening integer. For example, the number of carbonatoms in a (C1-C4)-alkyl group is 1, 2, 3, or 4. It should be understoodthat these designation refer to the total number of atoms in theappropriate group. For example, in a (C3-C10)-heterocyclyl the totalnumber of carbon atoms and heteroatoms is 3 (as in aziridine), 4, 5, 6(as in morpholine), 7, 8, 9, or 10.

“Pharmaceutically acceptable salt” or “salt” is used herein to refer toan agent or a compound according to the disclosure that is atherapeutically active, non-toxic base and acid salt form of thecompounds. The acid addition salt form of a compound that occurs in itsfree form as a base can be obtained by treating said free base form withan appropriate acid such as an inorganic acid, for example, a hydrohalicsuch as hydrochloric or hydrobromic, sulfuric, nitric, phosphoric andthe like; or an organic acid, such as, for example, acetic,hydroxyacetic, propanoic, lactic, pyruvic, malonic, succinic, maleic,fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic,benzenesulfonic, p-toluenesulfonic, cyclic, salicylic, p-aminosalicylic,pamoic and the like. See, e.g., WO 01/062726.

Compounds containing acidic protons may be converted into theirtherapeutically active, non-toxic base addition salt form, e.g. metal oramine salts, by treatment with appropriate organic and inorganic bases.Appropriate base salt forms include, for example, ammonium salts, alkaliand earth alkaline metal salts, e.g., lithium, sodium, potassium,magnesium, calcium salts and the like, salts with organic bases, e.g.N-methyl-D-glucamine, hydrabamine salts, and salts with amino acids suchas, for example, arginine, lysine and the like. Conversely, said saltforms can be converted into the free forms by treatment with anappropriate base or acid. Compounds and their salts can be in the formof a solvate, which is included within the scope of the presentdisclosure. Such solvates include for example hydrates, alcoholates andthe like. See, e.g., WO 01/062726.

Many of the compounds useful in the methods and compositions of thisdisclosure have at least one stereogenic center in their structure. Thisstereogenic center may be present in a R or a S configuration, said Rand S notation is used in correspondence with the rules described inPure Appl. Chem. (1976), 45, 11-30. The disclosure also relates to allstereoisomeric forms such as enantiomeric and diastereoisomeric forms ofthe compounds or mixtures thereof (including all possible mixtures ofstereoisomers). See, e.g., WO 01/062726.

Furthermore, certain compounds which contain alkenyl groups may exist asZ (zusammen) or E (entgegen) isomers. In each instance, the disclosureincludes both mixture and separate individual isomers. Multiplesubstituents on a piperidinyl or the azepanyl ring can also stand ineither cis or trans relationship to each other with respect to the planeof the piperidinyl or the azepanyl ring. Some of the compounds may alsoexist in tautomeric forms. Such forms, although not explicitly indicatedin the formulae described herein, are intended to be included within thescope of the present disclosure. With respect to the methods andcompositions of the present disclosure, reference to a compound orcompounds is intended to encompass that compound in each of its possibleisomeric forms and mixtures thereof unless the particular isomeric formis referred to specifically. See, e.g., WO 01/062726.

“Prodrug” or “pharmaceutically acceptable prodrug” refers to a compoundthat is metabolized, for example hydrolyzed or oxidized, in the hostafter administration to form the compound of the present disclosure(e.g., compounds of formula I or II). Typical examples of prodrugsinclude compounds that have biologically labile or cleavable(protecting) groups on a functional moiety of the active compound.Prodrugs include compounds that can be oxidized, reduced, aminated,deaminated, hydroxylated, dehydroxylated, hydrolyzed, dehydrolyzed,alkylated, dealkylated, acylated, deacylated, phosphorylated, ordephosphorylated to produce the active compound. Examples of prodrugsusing ester or phosphoramidate as biologically labile or cleavable(protecting) groups are disclosed in U.S. Pat. Nos. 6,875,751,7,585,851, and 7,964,580, the disclosures of which are incorporatedherein by reference. The prodrugs of this disclosure are metabolized toproduce a compound of formula I or II, which are agonists of the P₂Y₆receptor.

The disclosure further provides pharmaceutical compositions comprisingone or more compounds of the disclosure together with a pharmaceuticallyacceptable carrier or excipient.

UDP Derivatives and Compositions

The present disclosure provides a compound of formula I:

or a prodrug or salt thereof, wherein:

-   A is a 3- to 10-membered aromatic or non-aromatic ring having up to    5 heteroatoms independently selected from N, O, S, SO, or SO₂,    wherein the aromatic or non-aromatic ring is independently and    optionally substituted with one or more R⁷;-   X is independently selected from —O—, —S—, —N(R⁵)— and a    (C1-C3)-aliphatic group independently and optionally substituted    with one or more R⁴;-   Y is a bond or a (C1-C5)-aliphatic group independently and    optionally substituted with one or more R.-   Z and W are each independently selected from ═O, ═S, ═N(R⁵), and    ═NOR⁵;-   R¹ is selected from:    -   —H, halogen, —OR⁵, —CN, —CF₃, —OCF₃ and a (C1-C6)-aliphatic        group optionally substituted with one or more R⁷;-   R² and R³ are each independently selected from —OR⁵, —SR⁵, —NR⁵R⁶,    —OC(O)R⁵, —OC(O)NR⁵R⁶, and —OC(O)OR⁵; preferably, R² and R³ are each    independently selected from —OR⁵, —SR⁵, —NR⁵R⁶ and —OC(O)R⁵;-   each occurrence of R⁴ is independently selected from:    -   halogen, —OR⁵, —NO₂, —CN, —CF₃, —OCF₃, —R⁵, 1,2-methylenedioxy,        1,2-ethylenedioxy, —N(R⁵)₂, —SR⁵, —SOR⁵, —SO₂    -   R⁵, —SO₂N(R⁵)₂, —SO₃R⁵, —C(O)R⁵, —C(O)C(O)R⁵, —C(O)CH₂C(O)R⁵,        —C(S)R⁵, —C(S)O R⁵, —C(O)OR⁵, —C(O)C(O)OR⁵, —C(O)C(O)N(R⁵)₂,        —OC(O)R⁵, —C(O)N(R⁵)₂, —OC(O)N(R⁵)₂, —C(S)N(R⁵)₂,        —(CH₂)₀₋₂NHC(O)R⁵, —N(R⁵)N(R⁵)COR⁵, —N(R⁵)N(R⁵)C(O)OR⁵,        —N(R⁵)N(R⁵)CON(R⁵)₂, —N(R⁵) SO₂R⁵, —N(R⁵)SO₂N(R⁵)₂,        —N(R⁵)C(O)OR⁵, —N(R⁵)C(O)R⁵, —N(R⁵)C(S)R⁵, —N(R⁵)C(O) N(R⁵)₂,        —N(R⁵)C(S)N(R⁵)₂, —N(COR⁵)COR⁵, —N(OR⁵)R⁵, —C(═NH)N(R⁵)₂,        —C(O)N(OR⁵)R⁵, —C(═NOR⁵)R⁵, —OP(O)(OR⁵)₂, —P(O)(R⁵)₂,        —P(O)(OR⁵)₂, or —P(O)(H)(OR⁵);        each occurrence of R⁵ is independently selected from:    -   H—,    -   (C1-C12)-aliphatic-,    -   (C3-C10)-cycloalkyl- or -cycloalkenyl-,    -   [(C3-C10)-cycloalkyl or -cycloalkenyl]-(C1-C12)-aliphatic-,    -   (C6-C10)-aryl-,    -   (C6-C10)-aryl-(C1-C12)aliphatic-,    -   (C3-C10)-heterocyclyl-,    -   (C6-C10)-heterocyclyl-(C1-C12)aliphatic-,    -   (C5-C10)-heteroaryl-, and    -   (C5-C10)-heteroaryl-(C1-C12)-aliphatic-;    -   wherein two R⁵ groups bound to the same atom optionally form a        3- to 10-membered aromatic or non-aromatic ring having up to 3        heteroatoms independently selected from N, O, S, SO, or SO₂,        wherein said ring is optionally fused to a (C6-C10)aryl,        (C5-C10)heteroaryl, (C3-C10)cycloalkyl, or a        (C3-C10)heterocyclyl; and    -   wherein each R⁵ group is independently and optionally        substituted with one or more R⁷;        R⁶ is selected from:    -   —R⁵, —C(O)R⁵, —C(O)OR⁵, —C(O)N(R⁵)₂ and —S(O)₂R⁵;        each occurrence of R⁷ is independently selected from:    -   halogen, —OR⁸, —NO₂, —CN, —CF₃, —OCF₃, —R⁸, oxo, thioxo,        1,2-methylenedioxy, 1,2-ethylenedioxy, —N(R⁸)₂, —SR⁸, —SOR⁸,        —SO₂    -   R⁸, —SO₂N(R⁸)₂, —SO₃R⁸, —C(O)R⁸, —C(O)C(O)R⁸, —C(O)CH₂C(O)R⁸,        —C(S)R⁸, —C(S)O R⁸, —C(O)OR⁸, —C(O)C(O)OR⁸, —C(O)C(O)N(R⁸)₂,        —OC(O)R⁸, —C(O)N(R⁸)₂, —OC(O)N(R⁸)₂, —C(S)N(R⁸)₂,        —(CH₂)₀₋₂NHC(O)R⁸, —N(R⁸)N(R⁸)COR⁸, —N(R⁸)N(R⁸)C(O)OR⁸,        —N(R⁸)N(R⁸)CON(R⁸)₂, —N(R⁸)SO₂R⁸, —N(R⁸)SO₂N(R⁸)₂,        —N(R⁸)C(O)OR⁸, —N(R⁸)C(O)R⁸, —N(R⁸)C(S)R⁸, —N(R⁸)C(O)N(R⁸)₂,        —N(R⁸)C(S)N(R⁸)₂, —N(COR⁸)COR⁸, —N(OR⁸)R⁸, —C(═NH)N(R⁸)₂,        —C(O)N(O R⁸)R⁸, —C(═NOR⁸)R⁸, —OP(O)(OR⁸)₂, —P(O)(R⁸)₂,        —P(O)(OR⁸)₂, or —P(O)(H)(OR⁸);        each occurrence of R⁸ is independently selected from:    -   H— and (C1-C6)-aliphatic-.

In some embodiments, the salt is a pharmaceutically acceptable salt of acompound of formula I, such as a sodium salt.

In certain embodiments of compound of formula I, A is a(C5-C10)-aromatic ring having up to 5 heteroatoms independently selectedfrom N, O and S, wherein the aromatic ring is independently andoptionally substituted with one or more R⁷. In some embodiments, A is anoptionally substituted 5- or 6-membered aromatic ring having up to 2heteroatoms selected from N, O and S. In some embodiments, A is anoptionally substituted bi-cyclic aromatic ring having up to 4heteroatoms selected from N, O and S. For example, A is an aromaticgroup selected from:

wherein A is optionally further substituted with one or more R⁷.

In certain embodiments, A is selected from:

wherein A is optionally further substituted with one or more R⁷.

In some embodiments, A is

optionally further substituted with one or more R⁷.

In another embodiment, A is

optionally substituted with one or more R⁷. In some of the aboveembodiments of A, each occurrence of R⁷ is independently selected fromhalogen, —CF₃, —OCF₃, —C1-C4 aliphatic (e.g., —C1-C4 alkyl), and—O(C1-C4 aliphatic) (e.g., —O(C1-C4 alkyl)).

In certain embodiments, the present disclosure provides compounds offormula I, where X is —O—.

In some embodiments, the present disclosure also provides compounds offormula I, where R¹ is —H, bromine, iodine, methyl, ethyl or —CF₃. Insome embodiments, R¹ is —H.

According to certain embodiments, the present disclosure provides acompound of formula I, where Z is ═O or ═S. In some embodiments, Z is═O.

In some embodiments, the compound of the present disclosure has a W thatis ═O or ═S. In some embodiments, W is ═O.

According to certain embodiments, the present disclosure provides acompound of formula I, where Y is a C1-aliphatic group optionallysubstituted with one or more R⁴. For example, Y is —CH₂—. In someembodiments, Y is a C2-aliphatic group optionally substituted with oneor more R⁴. In some embodiments, Y is —CH₂—C(R⁴)₂—, such as —CH₂—CH₂—.In another embodiment, Y is —CH₂—C(R⁴)₂—, where each R⁴ is independentlyselected from halogen. In some embodiments, Y is —CH₂—C(R⁴)₂—, whereboth occurrences of R⁴ are —F. In another embodiment, Y is —CH₂—C(R⁴)₂—,where each occurrence of R⁴ is independently a (C1-C3)-aliphatic group.In yet another embodiment, Y is —CH₂—C(R⁴)₂—, where both occurrences ofR⁴ are —CH₃.

In some embodiments, the present disclosure provides a compound offormula I,

where R² and R³ are each independently —OR⁵. In some embodiments, R² is—OH. In another embodiment, R³ is —OH.

The disclosure also includes various combinations of A, X, Y, Z, W, R¹,R² and R³ as described above. These combinations can in turn be combinedwith any or all of the values of the other variables described above.For example, in some embodiments, Y is a C1- or C2-aliphatic groupoptionally substituted with one or more R⁴ and X is —O—. In anotherembodiment, Y is a C1- or C2-aliphatic group optionally substituted withone or more R⁴; X is —O—; and Z is ═O. In another embodiment, Y is a C1-or C2-aliphatic group optionally substituted with one or more R⁴; X is—O—; Z is ═O; and W is ═O. In yet another embodiment, Y is a C1- orC2-aliphatic group optionally substituted with one or more R⁴; X is —O—;Z is ═O; W is ═O; and R¹ is selected from —H, bromine, iodine, methyl,ethyl, and —CF₃, for example, R¹ is —H. In a further embodiment, Y is aC1- or C2-aliphatic group optionally substituted with one or more R⁴; Xis —O—; Z is ═O; W is ═O; and R¹ is selected from —H, bromine, iodine,methyl, ethyl, and —CF₃; and A is selected from the following groups:

wherein A is optionally further substituted with one or more R⁷, forexample, A is optionally substituted

In a further embodiment, Y is a C1- or C2-aliphatic group optionallysubstituted with one or more R⁴; X is —O—; Z is ═O; W is ═O; and R¹ isselected from —H, bromine, iodine, methyl, ethyl, and —CF₃; A isselected from the following group:

wherein A is optionally further substituted with one or more R⁷;and R² and R³ are each independently —OR⁵, for example, R² and R³ areeach independently —OH. In some of the above embodiments, eachoccurrence of R⁷ is independently selected from halogen, —CF₃, —OCF₃,—C1-C4 aliphatic (e.g., —C1-C4 alkyl), and —O(C1-C4 aliphatic) (e.g.,—O(C1-C4 alkyl)).

The present disclosure also provides a compound of formula II:

or a prodrug or salt thereof, wherein:

-   A is selected from:    -   a phenyl group that is substituted with at least one        (C1-C5)-aliphatic group or halogen;    -   a naphthalene group;    -   a 5- to 10-membered heteroaryl group having up to 5 heteroatoms        independently selected from N, O and S; and a 3- to 10-membered        non-aromatic ring having up to 5 heteroatoms independently        selected from N, O, S, SO, or SO₂;    -   wherein A is optionally further substituted with one or more R⁴;-   X is independently selected from —O—, —S—, —N(R⁵)— and a    (C1-C3)-aliphatic group independently and optionally substituted    with one or more R⁴;-   Y¹ is a (C1-C5)-aliphatic group substituted with at least one oxo    and further independently and optionally substituted with one or    more R⁴;-   Z and W are each independently selected from ═O, ═S, ═N(R⁵), and    ═NOR⁵;-   R¹ is selected from:    -   —H, halogen, —OR⁵, —CN, —CF₃, —OCF₃ and a        (C1-C6)-aliphatic-group optionally substituted with one or more        R⁴;-   R² and R³ are each independently selected from —OR⁵, —SR⁵, —NR⁵R⁶,    —OC(O)R⁵, —OC(O)NR⁵R⁶, and —OC(O)OR⁵; preferably, R² and R³ are each    independently selected from —OR⁵, —SR⁵, —NR⁵R⁶ and —OC(O)R⁵;    each occurrence of R⁴ is independently selected from:    -   halogen, —OR⁵, —NO₂, —CN, —CF₃, —OCF₃, —R⁵, oxo, thioxo,        1,2-methylenedioxy, 1,2-ethylenedioxy, —N(R⁵)₂, —SR⁵, —SOR⁵,        —SO₂    -   R⁵, —SO₂N(R⁵)₂, —SO₃R⁵, —C(O)R⁵, —C(O)C(O)R⁵, —C(O)CH₂C(O)R⁵,        —C(S)R⁵, —C(S)O R⁵, —C(O)OR⁵, —C(O)C(O)OR⁵, —C(O)C(O)N(R⁵)₂,        —OC(O)R⁵, —C(O)N(R⁵)₂, —OC(O)N(R⁵)₂, —C(S)N(R⁵)₂,        —(CH₂)₀₋₂NHC(O)R⁵, —N(R⁵)N(R⁵)COR⁵, —N(R⁵)N(R⁵)C(O)OR⁵,        —N(R⁵)N(R⁵)CON(R⁵)₂, —N(R⁵)SO₂R⁵, —N(R⁵)SO₂N(R⁵)₂,        —N(R⁵)C(O)OR⁵, —N(R⁵)C(O)R⁵, —N(R⁵)C(S)R⁵, —N(R⁵)C(O)N(R⁵)₂,        —N(R⁵)C(S)N(R⁵)₂, —N(COR⁵)COR⁵, —N(OR⁵)R⁵, —C(═NH)N(R⁵)₂,        —C(O)N(O R⁵)R⁵, —C(═NOR⁵)R⁵, —OP(O)(OR⁵)₂, —P(O)(R⁵)₂,        —P(O)(OR⁵)₂, or —P(O)(H)(OR⁵);        each occurrence of R⁵ is independently selected from:    -   H—,    -   (C1-C12)-aliphatic-,    -   (C3-C10)-cycloalkyl- or -cycloalkenyl-,    -   [(C3-C10)-cycloalkyl or -cycloalkenyl]-(C1-C12)-aliphatic-,    -   (C6-C10)-aryl-,    -   (C6-C10)-aryl-(C1-C12)aliphatic-,    -   (C3-C10)-heterocyclyl-,    -   (C6-C10)-heterocyclyl-(C1-C12)aliphatic-,    -   (C5-C10)-heteroaryl-, and    -   (C5-C10)-heteroaryl-(C1-C12)-aliphatic-;    -   wherein two R⁵ groups bound to the same atom optionally form a        3- to 10-membered aromatic or non-aromatic ring having up to 3        heteroatoms independently selected from N, O, S, SO, or SO₂,        wherein said ring is optionally fused to a (C6-C10)aryl,        (C5-C10)heteroaryl, (C3-C10)cycloalkyl, or a        (C3-C10)heterocyclyl; and    -   wherein each R⁵ group is independently and optionally        substituted with one or more R⁷;        R⁶ is selected from:    -   —R⁵, —C(O)R⁵, —C(O)OR⁵, —C(O)N(R⁵)₂ and —S(O)₂R⁵;        each occurrence of R⁷ is independently selected from:    -   halogen, —OR⁸, —NO₂, —CN, —CF₃, —OCF₃, —R⁸, oxo, thioxo,        1,2-methylenedioxy, 1,2-ethylenedioxy, —N(R⁸)₂, —SR⁸, —SOR⁸,        —SO₂    -   R⁸, —SO₂N(R⁸)₂, —SO₃R⁸, —C(O)R⁸, —C(O)C(O)R⁸, —C(O)CH₂C(O)R⁸,        —C(S)R⁸, —C(S)O R⁸, —C(O)OR⁸, —C(O)C(O)OR⁸, —C(O)C(O)N(R⁸)₂,        —OC(O)R⁸, —C(O)N(R⁸)₂, —OC(O)N(R⁸)₂, —C(S)N(R⁸)₂,        —(CH₂)₀₋₂NHC(O)R⁸, —N(R⁸)N(R⁸)COR⁸, —N(R⁸)N(R⁸)C(O)OR⁸,        —N(R⁸)N(R⁸)CON(R⁸)₂, —N(R⁸)SO₂R⁸, —N(R⁸)SO₂N(R⁸)₂,        —N(R⁸)C(O)OR⁸, —N(R⁸)C(O)R⁸, —N(R⁸)C(S)R⁸, —N(R⁸)C(O)N(R⁸)₂,        —N(R⁸)C(S)N(R⁸)₂, —N(COR⁸)COR⁸, —N(OR⁸)R⁸, —C(═NH)N(R⁸)₂,        —C(O)N(O R⁸)R⁸, —C(═NOR⁸)R⁸, —OP(O)(OR⁸)₂, —P(O)(R⁸)₂,        —P(O)(OR)₂, or —P(O)(H)(OR⁸);        each occurrence of R⁸ is independently selected from:    -   H— and (C1-C6)-aliphatic-.

In some embodiments, the salt is a pharmaceutically acceptable salt of acompound of formula II, such as a sodium salt.

In certain embodiments of compound of formula II, A is selected from thefollowing groups:

where A is optionally substituted with one or more R⁴.

In other embodiments of compound of formula II, A is selected from thefollowing groups:

where A is optionally substituted with one or more R⁴.

In such embodiments, A is one of the following groups:

where A is optionally further substituted with one or more R⁴.

In some embodiments, A is selected from:

where A is optionally further substituted with one or more R⁴.

In some embodiments, A is

where A is optionally further substituted with one or more R⁴.

In a further embodiment, A is

optionally substituted with one or more R⁴. In some of the aboveembodiments of A, each occurrence of R⁴ is independently selected fromhalogen, —CF₃, —OCF₃, —C1-C4 aliphatic (e.g., —C1-C4 alkyl), and—O(C1-C4 aliphatic) (e.g., —O(C1-C4 alkyl)).

In some embodiments, Y¹ is a C2-aliphatic group substituted with atleast one oxo and optionally further substituted with one or more R⁴,and A is selected from:

a phenyl group that is substituted with at least one (C1-C5)-aliphaticgroup or halogen;

a naphthalene group; and

a 6-membered monocyclic or a 9- to 10-membered bicyclic heteroaryl grouphaving up to 5 heteroatoms independently selected from N, O and S,wherein the bicyclic heteroaryl group has a 6-membered aryl orheteroaryl ring that is directly connected to Y¹;

wherein A is optionally further substituted with one or more R⁴. In somesuch embodiments, Y¹ is a C2-aliphatic group substituted with one oxo,and A is selected from:

wherein A is optionally further substituted with one or more R⁴.

According to certain embodiments, the present disclosure provides acompound of formula II, where X is —O—.

In some embodiments of the compound of formula II, R¹ is —H, bromine,iodine, methyl, ethyl or —CF₃. In some embodiments, R¹ is —H.

According to certain embodiments, the present disclosure also provides acompound of formula II, where Z is ═O or ═S. In some embodiments, Z is═O.

In some embodiments of the compound of formula II, W is ═O or ═S. Insome embodiments, W is ═O.

According to certain embodiments, the present disclosure also provides acompound of formula II, where Y¹ is a C1-aliphatic group substitutedwith oxo. In some embodiments, Y¹ is a C2-aliphatic group substitutedwith at least one oxo and optionally further substituted with one ormore R⁴. In another embodiment, Y¹ is —C(O)—C(R⁴)₂— or —C(R⁴)₂—C(O)—,for example, —C(O)—CH₂— or —CH₂—C(O)—. In a further embodiment, Y¹ is—C(O)—C(R⁴)₂— or —C(R⁴)₂—C(O)—, where each R⁴ is independently selectedfrom halogen. For example, Y¹ is —C(O)—C(R⁴)₂— or —C(R⁴)₂—C(O)—, whereboth occurrences of R⁴ in are —F. In yet another embodiment, Y¹ is—C(O)—C(R⁴)₂— or —C(R⁴)₂—C(O)—, where each R⁴ is independently a(C1-C3)-aliphatic group. For example, Y¹ is —C(O)—C(R⁴)₂— or—C(R⁴)₂—C(O)—, where both occurrences of R⁴ are —CH₃.

In some embodiments of compound of formula II, R² and R³ are eachindependently —OR⁵. In some embodiments, R² is —OH. In anotherembodiment, R³ is —OH.

The disclosure also includes various combinations of A, X, Y¹, Z, W, R¹,R² and R³ as described above. These combinations can in turn be combinedwith any or all of the values of the other variables described above.For example, in some embodiments, Y¹ is a C1-aliphatic group substitutedwith an oxo or a C2-aliphatic group substituted with at least one oxoand optionally further substituted with one or more R⁴ and X is —O—. Inanother embodiment, Y¹ is a C1-aliphatic group substituted with an oxoor a C2-aliphatic group substituted with at least one oxo and optionallyfurther substituted with one or more R⁴; X is —O—; and Z is ═O. Inanother embodiment, Y¹ is a C1-aliphatic group substituted with an oxoor a C2-aliphatic group substituted with at least one oxo and optionallyfurther substituted with one or more R⁴; X is —O—; Z is ═O; and W is ═O.In yet another embodiment, Y¹ is a C1-aliphatic group substituted withan oxo or a C2-aliphatic group substituted with at least one oxo andoptionally further substituted with one or more R⁴; X is —O—; Z is ═O; Wis ═O; and R¹ is selected from —H, bromine, iodine, methyl, ethyl, and—CF₃, for example, R¹ is —H. In a further embodiment. Y¹ is aC1-aliphatic group substituted with an oxo or a C2-aliphatic groupsubstituted with at least one oxo and optionally further substitutedwith one or more R⁴; X is —O—; Z is ═O; W is ═O; and R¹ is selected from—H, bromine, iodine, methyl, ethyl, and —CF₃; and A is selected from thefollowing groups:

wherein A is optionally further substituted with one or more R⁴, forexample, A is optionally further substituted

In yet a further embodiment, Y¹ is a C1-aliphatic group substituted withan oxo or a C2-aliphatic group substituted with at least one oxo andoptionally further substituted with one or more R⁴; X is —O—; Z is ═O; Wis ═O; and R¹ is selected from —H, bromine, iodine, methyl, ethyl, and—CF₃; A is selected from the following group:

wherein A is optionally further substituted with one or more R⁴;

and R² and R³ are each independently —OR⁵, for example, R² and R³ areeach independently —OH. In some of the above embodiments, eachoccurrence of R⁷ is independently selected from halogen, —CF₃, —OCF₃,—C1-C4 aliphatic (e.g., —C1-C4 alkyl), and —O(C1-C4 aliphatic) (e.g.,—O(C1-C4 alkyl)).

Examples of particular compounds of the present disclosure include:

or pharmaceutically acceptable salts thereof. In certain embodiments,the pharmaceutically acceptable salt is a sodium salt.

In another embodiment, the present disclosure provides a pharmaceuticalcomposition comprising a pharmaceutically acceptable carrier and acompound of formula I or II or pharmaceutically acceptable salt formthereof.

General Synthetic Methodology

The compounds of this disclosure may be prepared in general by methodsknown to those skilled in the art. Scheme 1 below illustrates a generalsynthetic route to the compounds of the present disclosure. Otherequivalent schemes, which will be readily apparent to the ordinaryskilled organic chemist, may alternatively be used to synthesize variousportions of the molecules as illustrated by the general scheme below.

Prodrugs of UDP Derivatives

The present disclosure provides a prodrug of a compound of formula I orII or pharmaceutically acceptable salt form thereof. In someembodiments, the prodrug of the instant application includesbiologically labile or cleavable protecting groups at one or bothphosphate groups of a compound of formula I or II, e.g., moieties thatare cleaved or hydrolyzed in the patient's body to generate the compoundof formula I or II or a salt thereof. In some embodiments, the prodrugsof the present disclosure can be oxidized, reduced, aminated,deaminated, hydroxylated, dehydroxylated, hydrolyzed, dehydrolyzed,alkylated, dealkylated, acylated, deacylated, phosphorylated, ordephosphorylated to produce the compound of formula I or II.

In certain embodiments, the prodrug includes two biologically labile orcleavable protecting groups on the terminal phosphate group of acompound of formula I or II. In other embodiments, the prodrug includesthree biologically labile or cleavable protecting groups on bothphosphate groups of a compound of formula I or II.

In certain embodiments, the prodrug of the present disclosure has theformula:

or a salt thereof,wherein:

-   -   A, X, Y, Z, W, R¹, R² and R³ are as defined above in formula I;    -   each n is independently 0-4; each occurrence of R^(1a) is a        group independently selected from aliphatic (such as        —(C1-C6)-alkyl), heterocyclyl, cycloalkyl, cycloalkenyl, aryl        and heteroaryl, wherein said aliphatic, heterocyclyl,        cycloalkyl, cycloalkenyl, aryl or heteroaryl is unsubstituted or        substituted with at least one R⁷ as defined above in formula I;        and    -   each occurrence of R^(1a′) is independently selected from —H and        R⁷ as defined above in formula I.

In some embodiments of prodrug-IA, at least one R^(1a) is an alkylgroup, such as methyl, ethyl, isopropyl or t-butyl. In some embodimentsof prodrug-IA, at least one R^(1a) is an optionally substituted phenyl.In preferred embodiments, n is 0. In certain embodiments of prodrug-IA,both occurrences of R^(1a) are the same.

In certain embodiments, the prodrug of the present disclosure has theformula:

or a salt thereof,wherein:

-   -   A, X, Y, Z, W, R¹, R² and R³ are as defined above in formula I;    -   each occurrence of R^(1b) is a group independently selected from        aliphatic (such as —(C1-C6)-alkyl), heterocyclyl, cycloalkyl,        cycloalkenyl, aryl and heteroaryl, wherein said aliphatic,        heterocyclyl, cycloalkyl, cycloalkenyl, aryl or heteroaryl is        unsubstituted or substituted with at least one R⁷ as defined        above in formula I; and    -   each occurrence of R^(1b′) is independently —H,        —(C1-C6)-aliphatic (such as —(C1-C6)-alkyl) or        —(C3-C6)-cycloalkyl; preferably, each occurrence of R^(1b′) is        independently —H or —(C1-C6)-aliphatic (such as —(C1-C6)-alkyl).

In some embodiments of prodrug-IB1 or prodrug-IB2, at least oneoccurrence of R^(1b) is an alkyl group, such as methyl, ethyl, isopropylor t-butyl. In some embodiments of prodrug-IB1 or prodrug-IB2, at leastone occurrence of R^(1b′) is —H. In certain embodiments of prodrug-IB1or prodrug-IB2, at least one occurrence of R^(1b′) is a —(C1-C6)-alkylgroup, such as methyl, ethyl or isopropyl. In some embodiments ofprodrug-IB1 or prodrug-IB2, all the occurrences of R^(1b) are the same.In some embodiments, all the occurrences of R^(1b′) are the same.

In certain embodiments, the prodrug of the present disclosure has theformula:

or a salt thereof,wherein:

-   -   A, X, Y, Z, W, R¹, R² and R³ are as defined above in formula I;        each occurrence of R^(1c) is a group independently selected from        aliphatic (such as —(C1-C6)-alkyl), heterocyclyl, cycloalkyl,        cycloalkenyl, aryl and heteroaryl, wherein said aliphatic,        heterocyclyl, cycloalkyl, cycloalkenyl, aryl or heteroaryl is        unsubstituted or substituted with at least one R⁷ as defined        above in formula I; and    -   each occurrence of R^(1c′) is independently —H,        —(C1-C6)-aliphatic (such as —(C1-C6)-alkyl) or        —(C3-C6)-cycloalkyl; preferably, each occurrence of R^(1c′) is        independently —H or —(C1-C6)-aliphatic (such as —(C1-C6)-alkyl).

In some embodiments of prodrug-IC1 or prodrug-IC2, at least oneoccurrence of R^(1c) is an alkyl group, such as methyl, ethyl, isopropylor t-butyl. In some embodiments of prodrug-IC1 or prodrug-IC2, at leastone occurrence of R^(1c′) is —H. In certain embodiments of prodrug-IC1or prodrug-IC2, at least one occurrence of R^(1c′) is a —(C1-C6)-alkylgroup, such as methyl, ethyl or isopropyl. In some embodiments ofprodrug-IC1 or prodrug-IC2, all the occurrences of R^(1c) are the same.In some embodiments, all the occurrences of R^(1c′) are the same.

In certain embodiments, the prodrug of the present disclosure has theformula:

or a salt thereof,wherein:

-   -   A, X, Y, Z, W, R¹, R² and R³ are as defined above in formula I;    -   R^(1d) is a group selected from aliphatic (such as        —(C1-C6)-alkyl), heterocyclyl, cycloalkyl, cycloalkenyl, aryl        and heteroaryl, wherein said aliphatic, heterocyclyl,        cycloalkyl, cycloalkenyl, aryl or heteroaryl is unsubstituted or        substituted with at least one R⁷ as defined above in formula I;    -   n is 0-5, preferably 0-2, most preferably 0; and    -   each occurrence of R^(1d′) is independently selected from —H and        R⁷ as defined above in formula I.

In some embodiments of prodrug-ID, R^(1d) is an alkyl group, such asmethyl, ethyl, isopropyl or t-butyl. In other embodiments of prodrug-ID,R^(1d) is an optionally substituted phenyl. In certain embodiments, n is0. In preferred embodiments where n is 1 or 2, all R^(1d′) are attachedto the carbon of the ring distal to the carbon bearing R^(1d)CO₂.

In certain embodiments, the prodrug of the present disclosure has theformula:

or a salt thereof,wherein:

-   -   A, X, Y, Z, W, R¹, R² and R³ are as defined above in formula I;    -   n is 0-4; and    -   each occurrence of R^(1e′) is independently selected from —H and        R⁷ as defined above in formula I.

In some embodiments of prodrug-IE, at least one occurrence of R^(1e) isa —(C1-C6)-alkyl group, such as methyl, ethyl, isopropyl or t-butyl. Insome embodiments of prodrug-IE, at least one occurrence of R^(1e) ishalogen, preferably —F or —Cl. In certain embodiments, n is 1. Incertain embodiments of prodrug-IE, n is 1 and R^(1e) is methyl.

In certain embodiments, the prodrug of the present disclosure has theformula:

or a salt thereof,wherein:

-   -   A, X, Y, Z, W, R¹, R² and R³ are as defined above in formula I;    -   R^(1fa) and R^(1fb) each independently is a group selected from        —H, aliphatic (such as —(C1-C6)-alkyl), heterocyclyl,        cycloalkyl, cycloalkenyl, aryl and heteroaryl, wherein said        aliphatic, heterocyclyl, cycloalkyl, cycloalkenyl, aryl or        heteroaryl is unsubstituted or substituted with at least one R⁷        as defined above in formula I; and    -   R^(1f′) and R^(1f″) each independently is a group selected from        —H, —(C1-C6)-aliphatic (such as —(C1-C6)-alkyl) and        —(C3-C6)-cycloalkyl; preferably, R^(1f′) and R^(1f″) each        independently is a group selected from —H or —(C1-C6)-aliphatic        (such as —(C1-C6)-alkyl).

In some embodiments of prodrug-IF, R^(1fa) is an alkyl group, such asmethyl, ethyl, isopropyl or t-butyl. In some embodiments of prodrug-IF,R^(1fa) is an optionally substituted phenyl. In some embodiments ofprodrug-IF, R^(1f′) is —H. In certain embodiments of prodrug-IF, R^(1f′)is a —(C1-C6)-alkyl group, such as methyl, ethyl or isopropyl. In someembodiments of prodrug-IF, R^(1f″) is —H. In certain embodiments ofprodrug-IF, R^(1f′) is a —(C1-C6)-alkyl group, such as methyl, ethyl orisopropyl, and R^(1f″) is —H.

In certain embodiments, the prodrug of the present disclosure has theformula:

Or a salt thereof,wherein:

-   X, Y¹, Z, W, R¹, R² and R³ are as defined above in formula II;-   A is selected from:    -   a phenyl group that is unsubstituted or substituted with at        least one (C1-C5)-aliphatic group or halogen;    -   a naphthalene group;    -   a 5- to 10-membered heteroaryl group having up to 5 heteroatoms        independently selected from N, O and S; and    -   a 3- to 10-membered non-aromatic ring having up to 5 heteroatoms        independently selected from N, O, S, SO, or SO₂;    -   wherein A is optionally further substituted with one or more R⁴;-   each n is independently 0-4;-   each occurrence of R^(2a) is a group independently selected from    aliphatic (such as —(C1-C6)-alkyl), heterocyclyl, cycloalkyl,    cycloalkenyl, aryl and heteroaryl, wherein said aliphatic,    heterocyclyl, cycloalkyl, cycloalkenyl, aryl or heteroaryl is    unsubstituted or substituted with at least one R⁴ as defined above    in formula II; and-   each occurrence of R^(2a′) is independently selected from —H and R⁴    as defined above in formula II.

In some embodiments of prodrug-IIA, at least one R^(2a) is an alkylgroup, such as methyl, ethyl, isopropyl or t-butyl. In some embodimentsof prodrug-IIA, at least one R^(2a) is an optionally substituted phenyl.In preferred embodiments, n is 0. In certain embodiments of prodrug-IIA,both occurrences of R^(2a) are the same.

In certain embodiments, the prodrug of the present disclosure has theformula:

or a salt thereof.wherein:

-   X, Y¹, Z, W, R¹, R² and R³ are as defined above in formula II;-   A is selected from:    -   a phenyl group that is unsubstituted or substituted with at        least one (C1-C5)-aliphatic group or halogen;    -   a naphthalene group;    -   a 5- to 10-membered heteroaryl group having up to 5 heteroatoms        independently selected from N, O and S; and    -   a 3- to 10-membered non-aromatic ring having up to 5 heteroatoms        independently selected from N, O, S, SO, or SO₂;        wherein A is optionally further substituted with one or more R⁴;-   each occurrence of R^(2b) is a group independently selected from    aliphatic (such as —(C1-C6)-alkyl), heterocyclyl, cycloalkyl,    cycloalkenyl, aryl and heteroaryl, wherein said aliphatic,    heterocyclyl, cycloalkyl, cycloalkenyl, aryl or heteroaryl is    unsubstituted or substituted with at least one R⁴ as defined above    in formula II; and-   each occurrence of R^(2b′) is independently —H, —(C1-C6)-aliphatic    (such as —(C1-C6)-alkyl) or —(C3-C6)-cycloalkyl; preferably, each    occurrence of R^(2b′) is independently —H or —(C1-C6)-aliphatic    (such as —(C1-C6)-alkyl).

In some embodiments of prodrug-IIB1 or prodrug-IIB2, at least oneoccurrence of R^(2b) is an alkyl group, such as methyl, ethyl, isopropylor t-butyl. In some embodiments of prodrug-IIB1 or prodrug-IIB2, atleast one occurrence of R^(2b′) is —H. In certain embodiments ofprodrug-IIB1 or prodrug-IIB2, at least one occurrence ofR^(2b′ is a —(C)1-C6)-alkyl group, such as methyl, ethyl or isopropyl.In some embodiments of prodrug-IIB1or prodrug-IIB2, all the occurrencesof R^(2b) are the same. In some embodiments, all the occurrences ofR^(2b′) are the same.

In certain embodiments, the prodrug of the present disclosure has theformula:

or a salt thereof,wherein:

-   X, Y¹, Z, W, R¹, R² and R³ are as defined above in formula II;-   A is selected from:    -   a phenyl group that is unsubstituted or substituted with at        least one (C1-C5)-aliphatic group or halogen;    -   a naphthalene group;    -   a 5- to 10-membered heteroaryl group having up to 5 heteroatoms        independently selected from N, O and S; and    -   a 3- to 10-membered non-aromatic ring having up to 5 heteroatoms        independently selected from N, O, S, SO, or SO₂;        wherein A is optionally further substituted with one or more R⁴;-   each occurrence of R^(2c) is a group independently selected from    aliphatic (such as —(C1-C6)-alkyl), heterocyclyl, cycloalkyl,    cycloalkenyl, aryl and heteroaryl, wherein said aliphatic,    heterocyclyl, cycloalkyl, cycloalkenyl, aryl or heteroaryl is    unsubstituted or substituted with at least one R⁴ as defined above    in formula II; and-   each occurrence of R^(2c′) is independently —H, —(C1-C6)-aliphatic    (such as —(C1-C6)-alkyl) or —(C3-C6)-cycloalkyl; preferably, each    occurrence of R^(2c″) is independently —H or —(C1-C6)-aliphatic    (such as —(C1-C6)-alkyl).

In some embodiments of prodrug-IIC1 or prodrug-IIC2, at least oneoccurrence of R^(2c) is an alkyl group, such as methyl, ethyl, isopropylor t-butyl. In some embodiments of prodrug-IIC1 or prodrug-IIC2, atleast one occurrence of R^(2c′) is —H. In certain embodiments ofprodrug-IIC1 or prodrug-IIC2, at least one occurrence of R^(2c′) is a—(C1-C6)-alkyl group, such as methyl, ethyl or isopropyl. In someembodiments of prodrug-IIC1or prodrug-IIC2, all the occurrences ofR^(2c) are the same. In some embodiments, all the occurrences of R^(2c′)are the same.

In certain embodiments, the prodrug of the present disclosure has theformula:

or a salt thereof,wherein:

-   X, Y¹, Z, W, R¹, R² and R³ are as defined above in formula II;-   A is selected from:    -   a phenyl group that is unsubstituted or substituted with at        least one (C1-C5)-aliphatic group or halogen;    -   a naphthalene group;    -   a 5- to 10-membered heteroaryl group having up to 5 heteroatoms        independently selected from N, O and S; and    -   a 3- to 10-membered non-aromatic ring having up to 5 heteroatoms        independently selected from N, O, S, SO, or SO₂;        wherein A is optionally further substituted with one or more R⁴;-   R^(2d) is a group selected from aliphatic (such as —(C1-C6)-alkyl),    heterocyclyl, cycloalkyl, cycloalkenyl, aryl and heteroaryl, wherein    said aliphatic, heterocyclyl, cycloalkyl, cycloalkenyl, aryl or    heteroaryl is unsubstituted or substituted with at least one R⁴ as    defined above in formula II;-   n is 0-5, preferably 0-2, most preferably 0; and-   each occurrence of R^(2d′) is independently selected from —H and R⁴    as defined above in formula II.

In some embodiments of prodrug-IID, R^(2d) is an alkyl group, such asmethyl, ethyl, isopropyl or t-butyl. In other embodiments ofprodrug-IID, R^(2d) is an optionally substituted phenyl. In certainembodiments, n is 0. In preferred embodiments where n is 1 or 2, allR^(2d′) are attached to the carbon of the ring distal to the carbonbearing R^(2d)CO₂.

In certain embodiments, the prodrug of the present disclosure has theformula:

or a salt thereof,wherein:

-   X, Y¹, Z, W, R¹, R² and R³ are as defined above in formula II;-   A is selected from:    -   a phenyl group that is unsubstituted or substituted with at        least one (C1-C5)-aliphatic group or halogen;    -   a naphthalene group;    -   a 5- to 10-membered heteroaryl group having up to 5 heteroatoms        independently selected from N, O and S; and    -   a 3- to 10-membered non-aromatic ring having up to 5 heteroatoms        independently selected from N, O, S, SO, or SO₂;        wherein A is optionally further substituted with one or more R⁴;-   n is 0-4; and-   each occurrence of R^(2e) is independently selected from —H and R⁴    as defined above in formula II.    In some embodiments of prodrug-IIE, at least one occurrence of    R^(2e) is a —(C1-C6)-alkyl group, such as methyl, ethyl, isopropyl    or t-butyl. In some embodiments of prodrug-IIE, at least one    occurrence of R^(2e) is halogen, preferably, —F or —Cl. In certain    embodiments, n is 1. In some embodiments of prodrug-IIE, n is 1 and    R^(2e) is methyl.

In certain embodiments, the prodrug of the present disclosure has theformula:

or salt thereof,wherein:

-   X, Y¹, Z, W, R¹, R² and R³ are as defined above in formula II;-   A is selected from:    -   a phenyl group that is unsubstituted or substituted with at        least one (C1-C5)-aliphatic group or halogen;    -   a naphthalene group;    -   a 5- to 10-membered heteroaryl group having up to 5 heteroatoms        independently selected from N, O and S; and    -   a 3- to 10-membered non-aromatic ring having up to 5 heteroatoms        independently selected from N, O, S, SO, or SO₂;        wherein A is optionally further substituted with one or more R⁴;-   R^(2fa) and R^(2fb) each independently is a group selected from —H,    aliphatic (such as —(C1-C6)-alkyl), heterocyclyl, cycloalkyl,    cycloalkenyl, aryl and heteroaryl, wherein said aliphatic,    heterocyclyl, cycloalkyl, cycloalkenyl, aryl or heteroaryl is    unsubstituted or substituted with at least one R⁴ as defined above    in formula II; and-   R^(2f′)and R^(2f″) each independently is a group selected from —H,    —(C1-C6)-aliphatic (such as —(C1-C6)-alkyl) and —(C3-C6)-cycloalkyl;    preferably, R^(2f′) and R^(2f″) each independently is a group    selected from —H or —(C1-C6)-aliphatic (such as —(C1-C6)-alkyl).

In some embodiments of prodrug-IIF. R^(2fa) is an alkyl group, such asmethyl, ethyl, isopropyl or t-butyl. In some embodiments of prodrug-IIF,R^(2fb) is an optionally substituted phenyl. In some embodiments ofprodrug-IIF, R^(2f′) is —H. In certain embodiments of prodrug-IIF,R^(2f′) is a —(C1-C6)-alkyl group, such as methyl, ethyl or isopropyl.In some embodiments of prodrug-IIF, R^(2f″) is —H. In certainembodiments of prodrug-IIF, R^(2f′) is a —(C1-C6)-alkyl group, such asmethyl, ethyl or isopropyl, and R^(2c″ is —H.)

For a compound of the formula I or II:

representative prodrugs of the present disclosure include:

or salts thereof. In some embodiments of the prodrug of the presentdisclosure, the salt is a sodium salt.

In another embodiment, the present disclosure provides a pharmaceuticalcomposition comprising a pharmaceutically acceptable carrier and aprodrug of a compound of formula I or II or pharmaceutically acceptablesalt form thereof.

The disclosure contemplates that any one or more of the foregoingaspects and embodiments can be combined with each other and/or with anyof the embodiments or features provided below.

Exemplary Uses

(1) Neuronal Diseases/Disorders

In certain aspects, the compounds, or salts and/or prodrugs thereof, andcompositions as described herein can be used to treat patients sufferingfrom P₂Y₆ receptor-related conditions, such as neurodegenerativediseases, and traumatic or mechanical injury to the central nervoussystem (CNS), spinal cord or peripheral nervous system (PNS). Many ofthese, as well as other conditions described herein, are characterizedby a level of cognitive impairment and/or some decrease or loss ofcognitive function. Cognitive function and cognitive impairment are usedas understood in the art. For example, cognitive function generallyrefers to the mental processes by which one becomes aware of, perceives,or comprehends ideas. Cognitive function involves all aspects ofperception, thinking, learning, reasoning, memory, awareness, andcapacity for judgment. Cognitive impairment generally refers toconditions or symptoms involving problems with thought processes. Thismay manifest itself in one or more symptoms indicating a decrease incognitive function, such as impairment or decrease of higher reasoningskills, forgetfulness, impairments to memory, learning disabilities,concentration difficulties, decreased intelligence, and other reductionsin mental functions.

Neurodegenerative disease typically involves reductions in the mass andvolume of the human brain, which may be due to the atrophy and/or deathof brain cells, which are far more profound than those in a healthyperson that are attributable to aging. Neurodegenerative diseases canevolve gradually, after a long period of normal brain function, due toprogressive degeneration (e.g., nerve cell dysfunction and death) ofspecific brain regions. Alternatively, neurodegenerative diseases canhave a quick onset, such as those associated with trauma or toxins. Theactual onset of brain degeneration may precede clinical expression bymany years. Examples of neurodegenerative diseases include, but are notlimited to, Alzheimer's disease (AD), Parkinson's disease (PD),Huntington's disease (HD), amyotrophic lateral sclerosis (ALS; LouGehrig's disease), diffuse Lewy body disease, chorea-acanthocytosis,primary lateral sclerosis, ocular diseases (ocular neuritis),chemotherapy-induced neuropathies (e.g., from vincristine, paclitaxel,bortezomib), diabetes-induced neuropathies and Friedreich's ataxia.P₂Y₆-modulating compounds, or salts and/or prodrugs thereof, of thepresent disclosure can be used to treat these disorders and others asdescribed below.

AD is a CNS disorder that results in memory loss, unusual behavior,personality changes, and a decline in thinking abilities. These lossesare related to the death of specific types of brain cells and thebreakdown of connections and their supporting network (e.g. glial cells)between them. The earliest symptoms include loss of recent memory,faulty judgment, and changes in personality. Without being bound bytheory, these changes in the brain and symptoms associated withcognitive impairment, including memory and learning impairment, arecaused, in whole or in part, by accumulation of beta amyloid and theresulting deposition of amyloid plaques. PD is a CNS disorder thatresults in uncontrolled body movements, rigidity, tremor, anddyskinesia, and is associated with the death of brain cells in an areaof the brain that produces dopamine. ALS (motor neuron disease) is a CNSdisorder that attacks the motor neurons, components of the CNS thatconnect the brain to the skeletal muscles.

HD is another neurodegenerative disease that causes uncontrolledmovements, loss of intellectual faculties, and emotional disturbance.Tay-Sachs disease and Sandhoff disease are glycolipid storage diseaseswhere GM2 ganglioside and related glycolipids substrates forβ-hexosaminidase accumulate in the nervous system and trigger acuteneurodegeneration.

It is well-known that apoptosis plays a role in AIDS pathogenesis in theimmune system. However, HIV-1 also induces neurological disease, whichcan be treated with P₂Y₆-modulating compounds, or salts and/or prodrugsthereof, of the disclosure.

Neuronal loss is also a salient feature of prion diseases, such asCreutzfeldt-Jakob disease in human, BSE in cattle (mad cow disease),Scrapie Disease in sheep and goats, and feline spongiform encephalopathy(FSE) in cats. P₂Y₆-modulating compounds, or salts and/or prodrugsthereof, as described herein, may be useful for treating or preventingneuronal loss due to these prion diseases.

In another embodiment, the compounds, or salts and/or prodrugs thereof,as described herein may be used to treat or prevent any disease ordisorder involving axonopathy. Distal axonopathy is a type of peripheralneuropathy that results from some metabolic or toxic derangement ofperipheral nervous system (PNS) neurons. It is the most common responseof nerves to metabolic or toxic disturbances, and as such may be causedby metabolic diseases such as diabetes, renal failure, deficiencysyndromes such as malnutrition and alcoholism, or the effects of toxinsor drugs. Those with distal axonopathies usually present withsymmetrical glove-stocking sensori-motor disturbances. Deep tendonreflexes and autonomic nervous system (ANS) functions are also lost ordiminished in affected areas.

Diabetic neuropathies are neuropathic disorders that are associated withdiabetes mellitus. Relatively common conditions which may be associatedwith diabetic neuropathy include third nerve palsy; mononeuropathy;mononeuritis multiplex; diabetic amyotrophy; a painful polyneuropathy;autonomic neuropathy; and thoracoabdominal neuropathy.

Peripheral neuropathy is the medical term for damage to nerves of theperipheral nervous system, which may be caused either by diseases of thenerve or from the side-effects of systemic illness. Major causes ofperipheral neuropathy include seizures, nutritional deficiencies, andHIV, though diabetes is the most likely cause.

In an exemplary embodiment, a P₂Y₆-modulating compound, or salt and/orprodrug thereof, as described herein may be used to treat or preventmultiple sclerosis (MS), including relapsing MS and monosymptomatic MS,and other demyelinating conditions, such as, for example, chronicinflammatory demyelinating polyneuropathy (CIDP), or symptoms associatedtherewith.

In yet another embodiment, compounds, or salts and/or prodrugs thereof,of the present disclosure may be used to treat trauma to the nerves,including, trauma due to disease, injury (including surgicalintervention), or environmental trauma (e.g., neurotoxins, alcoholism,etc.). In certain embodiments, compounds, or salts and/or prodrugsthereof, of the present disclosure may be used to treat traumatic braininjury, such as to improve cognitive function in a subject sufferingfrom a traumatic brain injury. Without being bound by theory, there isoften an increase in beta amyloid observed following traumatic braininjuries. The present disclosure provides methods suitable for enhancingclearance of beta amyloid or otherwise reducing beta amyloid and/orplaque burden in a subject.

Compounds, or salts and/or prodrugs thereof, of the present disclosuremay also be useful to prevent, treat, and alleviate symptoms of variousPNS disorders. The term “peripheral neuropathy” encompasses a wide rangeof disorders in which the nerves outside of the brain and spinalcord—peripheral nerves—have been damaged. Peripheral neuropathy may alsobe referred to as peripheral neuritis, or if many nerves are involved,the terms polyneuropathy or polyneuritis may be used.

PNS diseases treatable with P₂Y₆-modulating compounds, or salts and/orprodrugs thereof, as described herein, include: diabetes, leprosy,Charcot-Marie-Tooth disease, Guillain-Barré syndrome and Brachial PlexusNeuropathies (diseases of the cervical and first thoracic roots, nervetrunks, cords, and peripheral nerve components of the brachial plexus).

In another embodiment, compounds, or salts and/or prodrugs thereof, ofthe present disclosure may be used to treat or prevent a polyglutaminedisease. Exemplary polyglutamine diseases include Spinobulbar muscularatrophy (Kennedy disease), Huntington's Disease (HD),Dentatorubral-pallidoluysian atrophy (Haw River syndrome),Spinocerebellar ataxia type 1, Spinocerebellar ataxia type 2,Spinocerebellar ataxia type 3 (Machado-Joseph disease), Spinocerebellarataxia type 6, Spinocerebellar ataxia type 7, and Spinocerebellar ataxiatype 17.

In certain embodiments, the disclosure provides a method to treat acentral nervous system cell to prevent damage in response to a decreasein blood flow to the cell. Typically the severity of damage that may beprevented will depend in large part on the degree of reduction in bloodflow to the cell and the duration of the reduction. In some embodiments,apoptotic or necrotic cell death may be prevented. In still a furtherembodiment, ischemic-mediated damage, such as cytoxic edema or centralnervous system tissue anoxemia, may be prevented. In each embodiment,the central nervous system cell may be a spinal cell or a brain cell.

Another aspect encompasses administrating a compound, or salt and/orprodrug thereof, as described herein to a subject to treat a centralnervous system ischemic condition. A number of central nervous systemischemic conditions may be treated by the compounds, or salts and/orprodrugs thereof, described herein.

In some embodiments, the ischemic condition is a stroke that results inany type of ischemic central nervous system damage, such as apoptotic ornecrotic cell death, cytoxic edema or central nervous system tissueanoxia. The stroke may impact any area of the brain or be caused by anyetiology commonly known to result in the occurrence of a stroke. In onealternative of this embodiment, the stroke is a brain stem stroke. Inanother alternative of this embodiment, the stroke is a cerebellarstroke. In still another embodiment, the stroke is an embolic stroke. Inyet another alternative, the stroke may be a hemorrhagic stroke. In afurther embodiment, the stroke is a thrombotic stroke.

In yet another aspect, compounds, or salts and/or prodrugs thereof, ofthe disclosure may be administered to reduce infarct size of theischemic core following a central nervous system ischemic condition.Moreover, compounds, or salts and/or prodrugs thereof, of the presentdisclosure may also be beneficially administered to reduce the size ofthe ischemic penumbra or transitional zone following a central nervoussystem ischemic condition.

In some embodiments, a combination drug regimen may include drugs orcompounds for the treatment or prevention of neurodegenerative disordersor secondary conditions associated with these conditions. Thus, acombination drug regimen may include one or more compounds, or saltsand/or prodrugs thereof, as described herein and one or moreanti-neurodegeneration agents.

In a particular embodiment, the disclosure provides methods for doingone or more of decreasing plaque burden, improving cognitive function,decreasing or delaying cognitive impairment, or improving hippocampallong term potentiation by administering to a subject in need thereof aP₂Y₆ agonist. These methods may also be used for one or more ofenhancing beta amyloid clearance, increasing synaptic plasticity, orimproving or restoring memory. The foregoing are exemplary of beneficialresults that would help alleviate (e.g., treat) one or more symptoms ofconditions associated with cognitive impairment. Exemplary conditionsinclude AD, traumatic brain injury, and Down Syndrome, as well as otherneurological and neurodegenerative diseases. Moreover, the disclosurecontemplates the alleviation of symptoms in conditions and scenariosassociated with milder forms of cognitive impairment, such asage-related dementia, mild cognitive impairment, and even to improvememory and cognitive function that typically declines, even inrelatively healthy individuals, as part of the normal aging process.Exemplary such agonists, or salts and/or prodrugs thereof, are describedherein, and the disclosure contemplates that any such compounds, orsalts and/or prodrugs thereof can be used in the treatment of any of theconditions described herein. Regardless of whether one of the agonistsdescribed herein are used or whether another agonist is used, thedisclosure contemplates that the agonist may be formulated in apharmaceutically acceptable carrier and administered by any suitableroute of administration. These methods are of particular use when thesubject in need thereof has Alzheimer's disease. It is understood bythose of skill in the art that definitive diagnosis of Alzheimer'sdisease is difficult and may require post-mortem examination. Thus, inthis context and in the context of the present disclosure, havingAlzheimer's disease is used to refer to subjects who have been diagnosedwith Alzheimer's disease or who are suspected by a physician of havingAlzheimer's disease. However, these methods are also of particular usewhen the subject in need thereof has any other condition associated withcognitive impairment, for example, a condition in which the impairmentis accompanied with an increase in beta amyloid, a decrease in the rateof beta amyloid clearance, and/or an increase in amyloid plaquedeposition.

Cognitive function and cognitive impairment may be readily evaluatedusing tests well known in the art. Performance in these tests can becompared over time to determine whether a treated subject is improvingor whether further decline has stopped or slowed, relative to theprevious rate of decline of that patient or compared to an average rateof decline. Exemplary tests used in animal studies are provided in, forexample, Animal Models of Cognitive Impairment, Levin E D, Buccafusco JJ, editors. Boca Raton (FL): CRC Press; 2006. Tests of cognitivefunction, including memory and learning, for evaluating human patientsare well known in the art and regularly used to evaluate and monitorsubjects having or suspected of having cognitive disorders such as AD.Even in healthy individuals, these and other standard tests of cognitivefunction can be readily used to evaluate beneficial affects over time.

(2) Down Syndrome

Compounds or salts and/or prodrugs thereof, of the present disclosuremay also be useful to prevent, treat, and alleviate symptoms of DownSyndrome (DS). Down Syndrome (DS) is a genetic condition characterizedby trisomy of chromosome 21. DS is named after Dr. John Langdon Down, anEnglish physician who first described the characteristics of DS in 1866.It was not until 1959 that Jerome Leieune and Patricia Jacobsindependently first determined the cause to be trisomy of the 21stchromosome.

In recent years, it has become evident that there is relationshipbetween Alzheimer's Disease (AD) and DS. Specifically, the production ofexcessive beta amyloid plaques and amyloid angeopathy occurs in both DSand Alzheimer's Disease (AD) (Delabar et al. (1987) “Beta amyloid genetriplication in Alzheimer's disease and karyotypically normal DownSyndrome. Science 235: 1390-1392). Without being bound by theory, giventhat both AD and Down Syndrome are characterized by both beta amyloidplaques and cognitive impairment, methods and compositions that decreaseplaque burden and/or enhance beta amyloid clearance are useful fortreating AD and Down Syndrome (e.g., providing a beneficial effectand/or decreasing one or more symptoms of AD or Down Syndrome).Exemplary beneficial effects include, but are not limited to, improvingcognitive function, decreasing cognitive impairment, decreasing plaqueburden, enhancing beta amyloid clearance, improving memory, and thelike.

(3) Pain

In certain aspects, the compounds, or salts and/or prodrugs thereof, asdescribed herein can be used to treat patients having pain. Pain is acomplex physiological process that involves a number of sensory andneural mechanisms. Compounds, or salts and/or prodrugs thereof, to beused according to the present disclosure are suitable for administrationto a subject for treatment (including prevention and/or alleviation) ofchronic and/or acute pain, in particular non-inflammatorymusculoskeletal pain such as back pain, fibromyalgia and myofascialpain, more particularly for reduction of the associated muscularhyperalgesia or muscular allodynia. Nonlimiting examples of types ofpain that can be treated by the compounds, or salts and/or prodrugsthereof, compositions and methods of the present disclosure includechronic conditions such as musculoskeletal pain, including fibromyalgia,myofascial pain, back pain, pain during menstruation, pain duringosteoarthritis, pain during rheumatoid arthritis, pain duringgastrointestinal inflammation, pain during inflammation of the heartmuscle, pain during multiple sclerosis, pain during neuritis, painduring AIDS, pain during chemotherapy, tumor pain, headache, CPS(chronic pain syndrome), central pain, neuropathic pain such astrigeminal neuralgia, shingles, stamp pain, phantom limb pain,temporomandibular joint disorder, nerve injury, migraine, post-herpeticneuralgia, neuropathic pain encountered as a consequence of injuries,amputation infections, metabolic disorders or degenerative diseases ofthe nervous system, neuropathic pain associated with diabetes,pseudesthesia, hypothyroidism, uremia, vitamin deficiency or alcoholism;and acute pain such as pain after injuries, postoperative pain, painduring acute gout or pain during operations, such as jaw surgery.

Acute pain is typically a physiological signal indicating a potential oractual injury. Chronic pain can be somatogenic (organic) or psychogenic.Chronic pain is frequently accompanied or followed by vegetative signs,such as, for example, lassitude or sleep disturbance. Acute pain may betreated with compounds, or salts and/or prodrugs thereof, as describedherein.

Somatogenic pain may be of nociceptive, inflammatory or neuropathicorigin. Nociceptive pain is related to activation of somatic or visceralpain-sensitive nerve fibers, typically by physical or chemical injury totissues. Inflammatory pain results from inflammation, for example aninflammatory response of living tissues to any stimulus includinginjury, infection or irritation. Neuropathic pain results fromdysfunction in the nervous system. Neuropathic pain is believed to besustained by aberrant somatosensory mechanisms in the peripheral nervoussystem, the central nervous system (CNS), or both. According to oneaspect of the disclosure, somatogenic pain may be treated by compounds,or salts and/or prodrugs thereof, as described herein.

Non-inflammatory musculoskeletal pain is a particular form of chronicpain that is generally not traced to a specific structural orinflammatory cause and that generally does not appear to be induced bytissue damage and macrophage infiltration (resulting in edema) as occursin a classical immune system response. Although non-inflammatorymusculoskeletal pain is believed to result from peripheral and/orcentral sensitization, the cause is not presently fully understood. Itis often associated with physical or mental stress, lack of adequate orrestful sleep, or exposure to cold or damp. Non-inflammatorymusculoskeletal pain is also believed to be associated with orprecipitated by systemic disorders such as viral or other infections.Examples of non-inflammatory musculoskeletal pain include neck andshoulder pain and spasms, low back pain, and achy chest or thighmuscles, which may be treated by a compound, or salt and/or prodrugthereof, of the present disclosure. Non-inflammatory musculoskeletalpain may be generalized or localized.

According to a further aspect of the disclosure, a compound, or saltand/or prodrug thereof, as described herein may be administered to asubject to treat fibromyalgia syndrome (FMS) and myofascial painsyndrome (MPS). FMS and MPS are medical conditions characterized byfibromyalgia and myofascial pain respectively, which are two types ofnon-inflammatory musculoskeletal pain. FMS is a complex syndromeassociated with significant impairment of quality of life and can resultin substantial financial costs. Fibromyalgia is a systemic process thattypically causes tender points (local tender areas in normal-appearingtissues) in particular areas of the body and is frequently associatedwith a poor sleep pattern and/or stressful environment. Diagnosis offibromyalgia is typically based on a history of widespread pain (e.g.,bilateral, upper and lower body, and/or spinal pain), and presence ofexcessive tenderness on applying pressure to a number of (sometimes moreprecisely defined as at least 11 out of 18) specific muscle-tendersites. FMS is typically a chronic syndrome that causes pain andstiffness throughout the tissues that support and move the bones andjoints. Myofascial pain syndrome (MPS) is a chronic non-degenerative,non-inflammatory musculoskeletal condition often associated with spasmor pain in the masticatory muscles. Distinct areas within muscles ortheir delicate connective tissue coverings (fascia) become abnormallythickened or tight. When the myofascial tissues tighten and lose theirelasticity, the ability of neurotransmitters to send and receivemessages between the brain and body is disrupted. Specific discreteareas of muscle may be tender when firm fingertip pressure is applied;these areas are called tender or trigger points. Symptoms of MPS includemuscle stiffness and aching and sharp shooting pains or tingling andnumbness in areas distant from a trigger point. The discomfort may causesleep disturbance, fatigue and depression. Most commonly trigger pointsare in the jaw (temporomandibular) region, neck, back or buttocks.Myofascial pain differs from fibromyalgia: MPS and FMS are two separateentities, each having its own pathology, but sharing the muscle as acommon pathway of pain. Myofascial pain is typically a more localized orregional (along the muscle and surrounding fascia tissues) pain processthat is often associated with trigger point tenderness. Myofascial paincan be treated by a variety of methods (sometimes in combination)including stretching, ultrasound, ice sprays with stretching, exercises,and injections of anesthetic.

A further non-inflammatory musculoskeletal pain condition is back pain,notably low back pain, which may also be treated with a compound, orsalt and/or prodrug thereof, of the present disclosure. This conditionmay also be treating by administering a compound, or salt and/or prodrugthereof, of the present disclosure to a subject in need thereof. Backpain is a common musculoskeletal symptom that may be either acute orchronic. It may be caused by a variety of diseases and disorders thataffect the lumbar spine. Low back pain is often accompanied by sciatica,which is pain that involves the sciatic nerve and is felt in the lowerback, the buttocks, and the backs of the thighs.

Compositions and Modes of Administration

It will be appreciated that compounds and agents, or salts and/orprodrugs thereof, used in the compositions and methods of the presentdisclosure preferably should readily penetrate the blood-brain barrierwhen peripherally administered. Compounds which cannot penetrate theblood-brain barrier, however, can still be effectively administereddirectly into the central nervous system, e.g., by an intraventricularroute.

In some embodiments of this disclosure, the compound, or salt and/orprodrug thereof, of the present disclosure is formulated with apharmaceutically acceptable carrier. In other embodiments, no carrier isused. For example, the compound, or salt and/or prodrug thereof, asdescribed herein can be administered alone or as a component of apharmaceutical formulation (therapeutic composition). The compound, orsalt and/or prodrug thereof, may be formulated for administration in anyconvenient way for use in human medicine.

Pharmaceutically acceptable carriers that may be used in thesecompositions include, but are not limited to, ion exchangers, alumina,aluminum stearate, lecithin, serum proteins, such as human serumalbumin, buffer substances such as phosphates, glycine, sorbic acid,potassium sorbate, partial glyceride mixtures of saturated vegetablefatty acids, water, salts or electrolytes, such as protamine sulfate,disodium hydrogen phosphate, potassium hydrogen phosphate, sodiumchloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodiumcarboxymethylcellulose, polyacrylates, waxes,polyethylene-polyoxypropylene-block polymers, polyethylene glycol andwool fat.

In some embodiments, the therapeutic methods of the disclosure includeadministering the composition of a compound or agent, or salt and/orprodrug thereof, topically, systemically, or locally. For example,therapeutic compositions of compounds or agents, or salts and/orprodrugs thereof, of the disclosure may be formulated for administrationby, for example, injection (e.g., intravenously, subcutaneously, orintramuscularly), inhalation or insufflation (either through the mouthor the nose) or oral, buccal, sublingual, transdermal, nasal, orparenteral administration. The compositions of compounds or agents, orsalts and/or prodrugs thereof, described herein may be formulated aspart of an implant or device, or formulated for slow or extendedrelease. When administered parenterally, the therapeutic composition ofcompounds or agents, or salts and/or prodrugs thereof, for use in thisdisclosure is preferably in a pyrogen-free, physiologically acceptableform. Techniques and formulations generally may be found in Remington'sPharmaceutical Sciences, Meade Publishing Co., Easton, Pa.

In certain embodiments, pharmaceutical compositions suitable forparenteral administration may comprise the compound, or salt and/orprodrug thereof, of the present disclosure in combination with one ormore pharmaceutically acceptable sterile isotonic aqueous or non-aqueoussolutions, dispersions, suspensions or emulsions, or sterile powderswhich may be reconstituted into sterile injectable solutions ordispersions just prior to use, which may contain antioxidants, buffers,bacteriostats, solutes which render the formulation isotonic with theblood of the intended recipient or suspending or thickening agents.Examples of suitable aqueous and non-aqueous carriers which may beemployed in the pharmaceutical compositions of the disclosure includewater, ethanol, polyols (such as glycerol, propylene glycol,polyethylene glycol, and the like), and suitable mixtures thereof,vegetable oils, such as olive oil, and injectable organic esters, suchas ethyl oleate. Proper fluidity can be maintained, for example, by theuse of coating materials, such as lecithin, by the maintenance of therequired particle size in the case of dispersions, and by the use ofsurfactants.

A composition comprising a compound, or salt and/or prodrug thereof, ofthe present disclosure may also contain adjuvants, such aspreservatives, wetting agents, emulsifying agents and dispersing agents.Prevention of the action of microorganisms may be ensured by theinclusion of various antibacterial and antifungal agents, for example,paraben, chlorobutanol, phenol sorbic acid, and the like. It may also bedesirable to include isotonic agents, such as sugars, sodium chloride,and the like into the compositions. In addition, prolonged absorption ofthe injectable pharmaceutical form may be brought about by the inclusionof agents which delay absorption, such as aluminum monostearate andgelatin.

In certain embodiments of the disclosure, compositions comprising acompound, or salt and/or prodrug thereof, of the present disclosure canbe administered orally, e.g., in the form of capsules, cachets, pills,tablets, lozenges (using a flavored basis, usually sucrose and acacia ortragacanth), powders, granules, or as a solution or a suspension in anaqueous or non-aqueous liquid, or as an oil-in-water or water-in-oilliquid emulsion, or as an elixir or syrup, or as pastilles (using aninert base, such as gelatin and glycerin, or sucrose and acacia) and thelike, each containing a predetermined amount of the compound, or saltand/or prodrug thereof, of the present disclosure as an activeingredient.

In solid dosage forms for oral administration (capsules, tablets, pills,dragees, powders, granules, and the like), one or more compositionscomprising the compound, or salt and/or prodrug thereof, of the presentdisclosure may be mixed with one or more pharmaceutically acceptablecarriers, such as sodium citrate or dicalcium phosphate, and/or any ofthe following: (1) fillers or extenders, such as starches, lactose,sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as,for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and/or acacia; (3) humectants, such as glycerol;(4) disintegrating agents, such as agar-agar, calcium carbonate, potatoor tapioca starch, alginic acid, certain silicates, and sodiumcarbonate; (5) solution retarding agents, such as paraffin; (6)absorption accelerators, such as quaternary ammonium compounds; (7)wetting agents, such as, for example, cetyl alcohol and glycerolmonostearate; (8) absorbents, such as kaolin and bentonite clay; (9)lubricants, such a talc, calcium stearate, magnesium stearate, solidpolyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and(10) coloring agents. In the case of capsules, tablets and pills, thepharmaceutical compositions may also comprise buffering agents. Solidcompositions of a similar type may also be employed as fillers in softand hard-filled gelatin capsules using such excipients as lactose ormilk sugars, as well as high molecular weight polyethylene glycols andthe like.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, microemulsions, solutions, suspensions, syrups,and elixirs. In addition to the compound, or salt and/or prodrugthereof, of the present disclosure, the liquid dosage forms may containinert diluents commonly used in the art, such as water or othersolvents, solubilizing agents and emulsifiers, such as ethyl alcohol(ethanol), isopropyl alcohol, ethyl carbonate, ethyl acetate, benzylalcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils(in particular, cottonseed, groundnut, corn, germ, olive, castor, andsesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycolsand fatty acid esters of sorbitan, and mixtures thereof. Besides inertdiluents, the oral compositions can also include adjuvants such aswetting agents, emulsifying and suspending agents, sweetening,flavoring, coloring, perfuming, and preservative agents.

Suspensions, in addition to the active compounds, or salts and/orprodrugs thereof, may contain suspending agents such as ethoxylatedisostearyl alcohols, polyoxyethylene sorbitol, and sorbitan esters,microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agarand tragacanth, and mixtures thereof.

A person of ordinary skill in the art, such as a physician, is readilyable to determine the required amount of the compound, or salt and/orprodrug thereof, of the present disclosure to treat the subject usingthe compositions and methods of this disclosure. It is understood thatthe dosage regimen will be determined for an individual, taking intoconsideration, for example, various factors that modify the action of acompound, or salt and/or prodrug thereof, of the present disclosure, theseverity or stage of the disease, route of administration, andcharacteristics unique to the individual, such as age, weight, size, andextent of cognitive impairment.

It is well-known in the art that normalization to body surface area isan appropriate method for extrapolating doses between species. Tocalculate the human equivalent dose (HED) from a dosage used in thetreatment of age-dependent cognitive impairment in rats, the formula HED(mg/kg)=rat dose (mg/kg)×0.16 may be employed (see Estimating the SafeStarting Dose in Clinical Trials for Therapeutics in Adult HealthyVolunteers, December 2002, Center for Biologics Evaluation andResearch). For example, using that formula, a dosage of 10 mg/kg in ratsis equivalent to 1.6 mg/kg in humans. This conversion is based on a moregeneral formula HED=animal dose in mg/kg×(animal weight in kg/humanweight in kg)^(0.33). Similarly, to calculate the HED can be calculatedfrom a dosage used in the treatment in mouse, the formula HED(mg/kg)=mouse dose (mg/kg)×0.08 may be employed (see Estimating the SafeStarting Dose in Clinical Trials for Therapeutics in Adult HealthyVolunteers, December 2002, Center for Biologics Evaluation andResearch).

In certain embodiments of the disclosure, the dose of the compound, orsalt and/or prodrug thereof, or composition of the present disclosure isbetween 0.00001 and 100 mg/kg/day (which, given a typical human subjectof 70 kg, is between 0.0007 and 7000 mg/day).

In addition to compound, or salt and/or prodrug thereof, of the presentdisclosure, the compositions and methods of this disclosure can alsoinclude other therapeutically useful agents. These other therapeuticallyuseful agents may be administered in a single formulation,simultaneously or sequentially with the compound, or salt and/or prodrugthereof, of the present disclosure according to the methods of thedisclosure.

It will be understood by one of ordinary skill in the art that thecompositions and methods described herein may be adapted and modified asis appropriate for the application being addressed and that thecompositions and methods described herein may be employed in othersuitable applications, and that such other additions and modificationswill not depart from the scope hereof. For example, the compounds of thedisclosure are also useful as agents for agonizing P₂Y₆, and can be usedin vitro or in vivo to study normal and abnormal P₂Y₆ function.

This disclosure will be better understood from the Experimental Detailswhich follow. However, one skilled in the art will readily appreciatethat the specific methods and results discussed are merely illustrativeof the disclosure as described more fully in the embodiments whichfollow thereafter.

EXAMPLES Example 1 Preparation of Triethylamine and Sodium Salts ofCompound 6

Scheme 2 below provides a general synthetic route for the preparation ofthe triethylamine (TEA) and sodium salts of compound 6.

Step 1: Synthesis Of Compound 47

To a solution of compound 42 (3.0 g, 8.11 mmol) in DMF (90 mL) was addedY01 (3.0 g, 16.22 mmol) and K₂CO₃ (4.47 g, 16.22 mmol), the resultingmixture was stirred at 70° C. for 1 h. After cooling down, the mixturewas diluted with 250 mL water, extracted with ethyl acetate (EA) (250mL×3), the organic layer was dried over anhydrous Na₂SO₄, concentratedto give a crude product. The crude product was purified on column(eluted with PE/EA=3:1) to give 3.61 g 47 as a colorless oil, yield:94%. ¹H NMR (300 MHz, CDCl₃) δ 7.36 (d, J=8.1 Hz, 1H), 7.32-7.27 (m,4H), 7.25-7.18 (m, 1H), 5.98 (d, J=4.0 Hz, 1H), 5.81 (d, J=8.1 Hz, 1H),5.34 (d, J=2.4 Hz, 2H), 4.35 (s, 3H), 4.13 (m, 2H), 3.01-2.84 (m, 2H),2.14 (dd, J=12.1, 4.2 Hz, 9H), 1.26 (t, J=7.1 Hz, 1H).

Step 2: Synthesis of compound 48

3.61 g 47 was dissolved in 150 mL 5N NH₃/methanol then stirred at roomtemperature for 12 hrs. After the reaction was finished, methanol wasremoved under vacuum to give the crude product. The crude product wasrecrystallized from EA to give 1.94 g 48 as a white solid, yield: 73%.¹H NMR (300 MHz, DMSO) δ 7.95 (d, J=8.1 Hz, 1H), 7.37-7.11 (m, 5H), 5.77(m, 2H), 5.42 (d, J=5.4 Hz, 1H), 5.12 (m, 1H), 4.06-3.88 (m, 4H), 3.84(m, 1H), 3.64 (m, 1H), 3.53 (m, 1H), 2.80 (t, J=9.0 Hz, 2H).

Step 3: Synthesis of the Triethylamine (TEA) Salt of Compound 6

To a solution of compound 48 (500 mg, 1.44 mmol) in 7.2 mL trimethylphosphate was added proton sponge (460 mg, 2.15 mmol) under nitrogenatmosphere followed by POCl₃ (290 mg, 1.87 mmol) at 0° C. After 1 h ofstirring at 0-4° C., tri-n-butylamine (192 mg, 1.04 mmol) was added tothe solution followed by 7.2 mL of 0.5M tri-n-butylammonium phosphatesolution in dimethylformamide (DMF). After 5 min the mixture was pouredinto a cold 0.5M aqueous TEAB solution (45 mL, pH 7.5) and stirred at 0°C. for 10 min. The solution was allowed to warm to room temperature uponstirring and then left standing for 1 h. The mixture was extracted withtert-butyl methyl ether (50 mL×3), the aqueous solution was evaporatedand lyophilized to yield white solid. The white solid was purified onprep-HPLC to give 82.8 mg compound 6 TEA salt, yield: 7.1%. ¹H NMR (300MHz, D₂O) δ 7.82 (d, J=8.1 Hz, 1H), 7.23-7.08 (m, 5H), 5.83 (d, J=8.1Hz, 1H), 5.73 (d, J=4.0 Hz, 1H), 4.23-3.93 (m, 7H), 3.12-2.94 (m, 16H),2.78 (t, J=7.0 Hz, 2H), 1.14 (t, j=7.3 Hz, 24H).

Step 4: Synthesis of the Sodium Salt of Compound 6

82.8 mg compound 6 TEA salt was changed to sodium salt by ion exchangeresin to give Compound 6 sodium salt, 58.9 mg, yield: 100%. ¹H NMR (300MHz, D₂O) δ 7.84 (d, J=8.1 Hz, 1H), 7.20 (m, 5H), 5.87 (d, J=8.1 Hz,1H), 5.76 (d, J=4.3 Hz, 1H), 4.24-4.02 (m, 7H), 2.86 (t, J=7.1 Hz, 2H).³¹P NMR (162 MHz, D₂O) δ −9.68 (d, J=20.7 Hz, 1P), −11.00 (d, J=20.9 Hz,IP).

Example 2 Preparation of Triethylamine and Sodium Salts of Compound 3

Scheme 3 below provides a general synthetic route for the preparation ofthe triethylamine (TEA) and sodium salts of compound 3.

Step 1: Synthesis of compound 49

Compound 49 was prepared from compound 42 according to the sameprocedure as described in step 1 of Example 1. 2.98 g compound 49 wasobtained from 3.0 g compound 42, yield: 79.7%. ¹H NMR (300 MHz, CDCl₃) δ8.47 (d, J=4.7 Hz, 1H), 7.58 (m, 1H), 7.43 (d, J=8.2 Hz, 1H), 7.19-7.07(m, 2H), 6.01 (d, J=4.8 Hz, 1H), 5.85 (d, J=8.2 Hz, 1H), 5.36-5.26 (m,2H), 5.20 (s, 2H), 4.31 (s, 3H), 2.05 (t, J=10.5 Hz, 9H).

Step 2: Synthesis of compound 50

Compound 50 was prepared from compound 49 according to the sameprocedure as described in step 2 of Example 1. 1.79 g compound 50 wasobtained from 2.98 g compound 49, yield: 82.7%. ¹H NMR (300 MHz, DMSO) δ8.42 (d, J=3.5 Hz, 1H), 8.03 (d, J=8.1 Hz, 1H), 7.76-7.67 (m, 1H),7.26-7.18 (m, 2H), 5.81 (dd, J=14.9, 6.5 Hz, 2H), 5.44 (d, J=5.7 Hz,1H), 5.23-5.01 (m, 4H), 4.03 (m, 1H), 3.96 (m, 1H), 3.84 (m, 1H),3.70-3.59 (m, 1H), 3.53 (m, 1H).

Step 3: Synthesis of the TEA Salt of Compound 3

The TEA salt of compound 3 was prepared from compound 50 according tothe same procedure as described in step 3 of Example 1. 8.6 mg compound3 TEA salt was obtained from 100 mg compound 50, yield: 4%. ¹H NMR (300MHz, D₂O) δ 8.38-8.26 (m, 1H), 7.96 (d, J=8.2 Hz, 1H), 7.74 (m, 1H),7.34-7.19 (m, 2H), 5.94 (m, 2H), 5.13 (d, J=2.8 Hz, 2H), 4.32-4.27 (m,2H), 4.21-4.11 (m, 3H), 3.08 (q, J=7.3 Hz, 13H), 1.16 (t, J=7.3 Hz,23H).

Step 4: Synthesis of the Sodium Salt of Compound 3

The sodium salt of compound 3 was prepared from the TEA salt of compound3 according to the same procedure as described in step 4 of Example 1.24.9 mg compound 3 sodium salt was obtained from 31 mg compound 3 TEAsalt, yield: 99%. ¹H NMR (300 MHz, D₂O) δ 8.31 (d, J=4.4 Hz, 1H), 7.98(d, J=8.1 Hz, 1H), 7.73 (t, J=7.8 Hz, 1H), 7.25 (d, J=7.7 Hz, 2H), 6.01(d, J=8.1 Hz, 1H), 5.86 (d, J=3.8 Hz, 1H), 5.12 (s, 2H), 4.28 (m, 5H).³¹P NMR (162 MHz, D₂O) δ −6.73 (d, J=21.9 Hz), −10.54 (d, J=21.9 Hz).

Example 3 Preparation of Triethylamine and Sodium Salts of Compound 4

Scheme 4 below provides a general synthetic route for the preparation ofthe triethylamine (TEA) and sodium salts of compound 4.

Step 1: Synthesis of compound 51

To a solution of compound 42 (1.061 g, 1.87 mmol), Y03 (930 mg, 5.73mmol) and PPh₃ (1.501 g, 5.73 mmol) in 25 mL THF was added dropwise asolution of DIAD (1.159 g, 5.73 mmol) in 5 mL THF over 30 min, theresulting mixture was stirred at 50° C. for 3 h. After the reaction wasfinished, THF was removed to give the crude product. The crude productwas purified on column (eluted with EA) to give 1.37 g compound 51 as anoil, yield: 88.8%.

Step 2: Synthesis of Compound 52

Compound 52 was prepared from compound 51 according to the sameprocedure as described in step 2 of Example 1. 0.8 g compound 52 wasobtained from 1.37 g compound 51, yield: 77.4%. ¹H NMR (300 MHz, DMSO) δ7.99 (d, J=8.1 Hz, 1H), 7.73 (d, J=8.2 Hz, 1H), 7.55 (d, J=8.5 Hz, 1H),7.36 (t, J=7.7 Hz, 1H), 7.09 (t, J=7.5 Hz, 1H), 5.87-5.76 (m, 2H), 5.38(d, J=5.7 Hz, 1H), 5.30 (d, J=4.0 Hz, 2H), 5.12-5.06 (m, 1H), 4.01 (t,J=5.2 Hz, 1H), 3.94 (s, 4H), 3.84 (d, J=3.6 Hz, 1H), 3.68-3.46 (m, 2H).

Step 3: Synthesis of the TEA Salt of Compound 4

The TEA salt of compound 4 was prepared from compound 52 according tothe same procedure as described in step 3 of Example 1. 8.1 mg compound4 TEA salt was obtained from 100 mg compound 52, yield: 4%. ¹H NMR (300MHz, D₂O) δ 7.91 (d, J=8.1 Hz, 1H), 7.68 (d, J=8.2 Hz, 1H), 7.43-7.34(m, 2H), 7.11 (m, 1H), 5.98 (d, J=8.1 Hz, 1H), 5.88 (d, J=4.2 Hz, 1H),5.32 (d, J=1.9 Hz, 2H), 4.26 (m, 2H), 4.15 (m, 3H), 3.86 (s, 3H), 3.07(q, J=7.3 Hz, 12H), 1.23-1.09 (t, J=7.3 Hz, 20H).

Step 4: Synthesis of the sodium salt of compound 4

The sodium salt of compound 4 was prepared from the TEA salt of compound4 according to the same procedure as described in step 4 of Example 1.64.3 mg compound 4 sodium salt was obtained from 80 mg compound 4 TEAsalt, yield: 98%. ¹H NMR (300 MHz, D₂O) δ 7.74 (d, J=8.1 Hz, 1H), 7.32(d, J=8.0 Hz, 1H), 6.96 (m, 1H), 6.79 (m, 2H), 5.84 (d, J=8.1 Hz, 1H),5.73 (d, J=4.1 Hz, 1H), 4.92 (s, 2H), 4.29-4.06 (m, 5H), 3.55 (s, 3H).³¹NMR (162 MHz, D₂O) δ −9.88 (d, J=19.7 Hz, IP), −10.82 (d, J=19.7 Hz,IP).

Example 4 Preparation of Triethylamine and Sodium Salts of Compound I

Scheme 5 below provides a general synthetic route for the preparation ofthe triethylamine (TEA) and sodium salts of compound I.

Step 1: Synthesis of Compound 53

Compound 53 was prepared from compound 42 according to the sameprocedure as described in step 1 of Example 1. A crude product ofcompound 53 was obtained from 1.14 g compound 42. The crude product wasused in the next step directly without further purification.

Step 2: Synthesis of Compound 54

Compound 54 was prepared from compound 53 according to the sameprocedure as described in step 2 of Example 1. 700 mg compound 54 wasobtained from the 1.14 g compound 53, yield: 59.2%. ¹H NMR (300 MHz,DMSO) δ 7.99 (d, J=9.0 Hz, 1H), 7.46-7.52 (m, 5H), 5.72-5.82 (m, 2H),5.07-5.10 (m, 1H), 4.45-4.55 (m, 2H), 3.92-4.00 (m, 2H), 3.86 (s, 1H),3.54-3.64 (m, 2H), 3.30-3.32 (m, 1H).

Step 3: Synthesis of the TEA Salt of Compound I

The TEA salt of compound I was prepared from compound 54 according tothe same procedure as described in step 3 of Example 1. 8.6 mg compoundI TEA salt was obtained from 100 mg compound 54, yield: 5%. ¹H NMR (300MHz, D₂O) δ 7.80 (d, J=8.2 Hz, 1H), 7.41 (m, 5H), 5.85 (d, J=8.2 Hz,1H), 5.72 (d, J=4.4 Hz, 1H), 4.49 (m, 2H), 4.12 (m, 6H), 3.07 (q, J=7.3Hz, 4H), 1.16 (t, J=7.3 Hz, 6H).

Step 4: Synthesis of the Sodium Salt of Compound 1

The sodium salt of compound I was prepared from the TEA salt of compoundI according to the same procedure as described in step 4 of Example 1.28.3 mg compound I sodium salt was obtained from 30 mg compound I TEAsalt, yield: 100%. ¹H NMR (300 MHz, D₂O) δ 7.88 (d, J=8.2 Hz, 1H),7.50-7.38 (m, 5H), 5.89 (d, J=8.2 Hz, 1H), 5.73 (d, J=4.1 Hz, 1H), 4.55(m, 2H), 4.31-4.04 (m, 5H). ³¹P NMR (162 MHz, D₂O) δ −8.13 (d, J=21.6Hz, 1P), −10.86 (d, J=21.7 Hz, 1P).

Example 5 Preparation of Triethylamine and Sodium Salts of Compound 5

Scheme 5 below provides a general synthetic route for the preparation ofthe triethylamine (TEA) and sodium salts of compound 5.

Step 1: Synthesis of compound 55

Compound 55 was prepared from compound 42 according to the sameprocedure as described in step 1 of Example 1. 4.2 g compound 55 wasobtained from 3.0 g compound 42, yield: 100%. ¹H NMR (300 MHz, CDCl₃) δ7.79 (d, J=8.0 Hz, 1H), 7.53 (dd, J=3.7, 1.6 Hz, 2H), 7.45 (d, J=8.2 Hz,1H), 7.30 (m, 1H), 6.04 (d, J=4.7 Hz, 1H), 5.89 (d, J=8.2 Hz, 1H), 5.50(d, J=1.7 Hz, 2H), 5.33 (m, 2H), 4.34 (d, J=4.3 Hz, 3H), 2.10 (d, J=6.6Hz, 6H), 2.04 (s, 3H).

Step 2: Synthesis of Compound 56

Compound 56 was prepared from compound 55 according to the sameprocedure as described in step 2 of Example 1. 2.36 g compound 56 wasobtained from 4.2 g compound 55, yield: 75.6%. ¹H NMR (300 MHz, DMSO) δ8.06 (d, J=8.2 Hz, 2H), 7.86 (d, J=8.0 Hz, 2H), 7.76-7.61 (m, 4H), 7.39(t, J=7.4 Hz, 2H), 5.89 (d, J=7.9 Hz, 2H), 5.80 (m, 2H), 5.38-5.42 (m,3H), 5.16 (m, 1H), 3.85-4.04 (m, 2H), 3.50-3.66 (m, 2H).

Step 3: Synthesis of the TEA Salt of Compound 5

The TEA salt of compound 5 was prepared from compound 56 according tothe same procedure as described in step 3 of Example 1. 26.3 mg compound5 TEA salt was obtained from 300 mg compound 56, yield: 5%. ¹H NMR (300MHz, D₂O) δ 7.80 (d, J=8.2 Hz, 1H), 7.51 (d, J=7.9 Hz, 1H), 7.42-7.35(m, 1H), 7.31 (m, 1H), 7.12 (t, J=7.3 Hz, 1H), 5.90 (d, J=8.2 Hz, 1H),5.80 (d, J=4.0 Hz, 1H), 5.22 (s, 2H), 4.27-4.00 (m, 6H), 2.98 (q, J=7.3Hz, 7H), 1.07 (t, J=7.3 Hz, 10H).

Step 4: Synthesis of the Sodium Salt of Compound 5

The sodium salt of compound 5 was prepared from the TEA salt of compound5 according to the same procedure as described in step 4 of Example 1.51.5 mg compound 5 sodium salt was obtained from 55 mg compound 5 TEAsalt, yield: 99%. ¹H NMR (300 MHz, D₂O) δ 7.98 (d, J=8.2 Hz, 1H), 7.75(d, J=8.0 Hz, 1H), 7.63-7.54 (m, 2H), 7.35 (m, 1H), 6.03 (d, J=8.2 Hz,1H), 5.89 (d, J=4.2 Hz, 1H), 5.45 (s, 2H), 4.31 (m, 2H), 4.15 (m, 3H).³¹P NMR (162 MHz, D₂O) δ −7.95 (d, J=21.2 Hz, 1P), −10.80 (d, J=21.5 Hz,1P).

The sodium salts of compounds 44-49 were prepared according to similarsynthetic procedures as those used for preparing compound 5 (see Scheme5 above). The characterization of these sodium salts are summarized inTable 1 below.

TABLE 1 Characterization of compounds 44-49: Compound Characterization

44 White solid, yield: 3% ¹H NMR (400 MHz, D2O): δ 7.92 (1H, d, J = 8Hz), 7.51-7.52 (1H, m), 7.21-7.25 (1H, m), 7.01-7.06 (1H, m), 5.98 (1H,d, J = 8.4 Hz), 5.88 (1H, d, J = 4 Hz), 5.38 (2H, s), 4.25-4.24 (2H, m),4.16-4.11 (3H, m), ³¹P NMR (400 MHz, D2O): δ −10.78 (1P, d, J = 15.4Hz), −11.36 (1P, d, J = 15.5 Hz).

45 White solid, yield: 3% ¹H NMR (400 MHz, D2O): δ 8.01 (1H, d, J = 8Hz), 7.58-7.56 (1H, m), 7.40-7.31 (2H, m), 6.04 (1H, d, J = 8.4 Hz),5.90 (1H, s), 5.48 (1H, s), 4.37-4.30 (2H, m), 4.18-4.17(3H, m). ³¹P NMR(400 MHz, D2O): δ −6.87 (1P, d, J = 16.1 Hz), −10.91 (1P, d, J = 16.7Hz).

46 White solid, yield: 4.6% ¹H NMR (400 MHz, D2O): δ 8.02 (1H, d, J = 8Hz), 7.48 (1H, d, J = 7.2 Hz), 7.38 (1H, d, J = 8.4 Hz), 7.14 (1H, d, J= 7.2 Hz), 6.05 (1H, d, J = 8.0 Hz), 5.90 (1H, s), 5.60 (1H, s),4.34-4.31 (2H, m), 4.22-4.20 (3H, m). ³¹P NMR (400 MHz, D2O): δ −5.79(1P, d, J = 14.2 Hz), −10.01 (1P, d, J = 13.7 Hz).

47 White solid, yield: 5.3% ¹H NMR (400 MHz, D2O): δ 7.98 (1H, d, J = 8Hz), 7.44 (1H, s), 7.39 (1H, s), 6.01 (1H, d, J = 8.0 Hz), 5.86 (1H, d,J = 4.0 Hz), 5.37 (2H, s), 4.35-4.33 (1H, m), 4.28-4.26 (1H, m),4.16-4.15 (3H, m). ³¹P NMR (400 MHz, D2O): δ −6.57 (1P, d, J = l6.7 Hz),−10.87 (1P, d, J = 16.7 Hz).

48 White solid, yield: 5.3% ¹H NMR (400 MHz, D2O): δ 7.96 (1H, d, J = 8Hz), 7.57 (1H, d, J = 8 Hz), 7.35 (1H, s), 7.16 (1H, d, J = 8 Hz), 6.01(1H, d, J = 8.0 Hz), 5.89 (1H, d, J = 4.0 Hz), 5.40 (2H, s), 4.30-4.26(2H, m), 4.18-4.11 (3H, m), 2.40 (3H, s). ³¹P NMR (400 MHz, D2O): δ−10.35 (1P, d, J = 15.3 Hz), −11.32 (1P, d, J = 15.4 Hz).

49 White solid, yield: 3% ¹H NMR (400 MHz, D2O): δ 7.97 (1H, d, J = 8Hz), 7.51 (1H, d, J = 8 Hz), 7.35 (1H, d, J = 8 Hz), 7.21 (1H, d, J = 8Hz), 6.03 (1H, d, J = 8.0 Hz), 5.91 (1H, d, J = 4.0 Hz), 5.41 (2H, s),4.30-4.28 (2H, m), 4.21-4.12 (3H, m), 2.40 (3H, s). ³¹P NMR (400 MHz,D2O): δ −10.73 (1P, d, J = 15.3 Hz), −11.33 (1P, d, J = 15.1 Hz).

Example 6 Materials and Methods for In Vitro and In Vivo Studies

Activation of P₂Y₆ Receptor

Synthetic ligands were tested for activation of P₂Y₆ receptor bymeasuring receptor induced Ca²⁺ changes with the fluorescent Ca²⁺indicator fluo-4. 1321N1 human astrocytoma cell lines either expressingP₂Y₂, P₂Y₄ or P₂Y₆ receptors were plated into 24-well plates. Two daysafter plating, fluorometric measurements were made and responses ofcells to a serial dilution of ligands were determined. P₂Y₆ mediatedCa²⁺ fluorescent change was determined by normalized accumulation offluorescent change of 3 timepoints after ligand administrationsubtracted by value from ACSF control. Changes in fluorescent intensitywere plotted corresponding to ligand concention in GraphPad.Dose-response curve and EC₅₀ for each ligand was estimated usingnonlinear curve fit and Sigmoidal dose-response analysis. The sodiumsalt of compound 5 exhibited an EC₅₀ of 12 nM. The sodium salt ofcompound 5 was demonstrated to selectively activate P₂Y₆ receptors bycomparing its Ca²⁺ mobilizing effects in three 1321N1 human astrocytomacell lines expressing P₂Y₂, P₂Y₄ or P₂Y₆ receptors. The sodium salt ofcompound 5 was only effective at elevating Ca²⁺ levels when applied tocells expressing P₂Y₆ receptors and not effective in P₂Y₂, or P₂Y₄receptor expressing cells. The ability of the sodium salt of compound 5to elevate Ca²⁺ signals in P₂Y₆ expressing cells was attenuated byaddition of the P₂Y₆ antagonist MR2578.

PSAPP Mice

Heterozygous mutant (K670N/M671L) APP (50% C57B6, 50% SJL) transgenicmice were crossed with heterozygous mutant (A246E) PS-1 (50% C57B6, 50%SJL) transgenic mice to generate heterozygous PSAPP transgenic mice(also referred to as PS-1/APP or PSAPP+/+ mice), which refers to animalsheterozygous for the PS-1 A246E transgene and the APP K670N/M671Ltransgene. Non-transgenic control animals were littermates (alsoreferred to as PSAPP_−/− mice) generated in the breeding for PSAPPtransgenic animals. Mouse genotype was determined by Polymerase ChainReaction (PCR). Both male and female mice of 6-7 months old were usedfor the experiments below. All animal experiments were performed inaccordance with the Tufts Animal Care and Use Committee and withnational regulations and policies.

Two-Photon In Vivo Imaging Study

In this study, PSAPP mice were anesthetized using isoflurane and athin-skull preparation was used to minimize the surface damage. Amyloidplaques were visualized with methoxyX04 labeling and blood plasma waslabeled with Rhodamine dextran to facilitate re-localization of the sameimaging area. Stack images were obtained using a two-photon system(Prairie Technologies) with excitation at 850 nm. The emission wasdetected by external photomultiplier tubes (525/70; DLCP 575; 607/45nm).

Stereotaxic Injection

Animals were anesthetized and immobilized in a stereotaxic frame. Foreach injection, 1 μl of 10 mM UDP or other suitable compounds inartificial cerebrospinal fluid (ACSF) as the vehicle were injectedintraventricularly using the following coordinates: AP 0.2 mm, ML 1 mm,and DV 2.2 mm.

Histology and Immunohistochemistry

Mice were perfused transcardially with 4% paraformaldehyde and 40 μmCoronal sections were collected. Sections were sequentially incubated in0.3% H₂O₂ for 10 minutes, blocking solution for 2 hrs, blocking solutioncontaining the primary antibody (rabbit anti-beta1-42; rabbit anti-beta1-40, from Chemicon International and rat anti-CD45) for 48 hours at 4°C., and blocking solution containing biotinylated antibody orfluorescently-labeled antibody for 2 hours at room temperature. Sectionswere visualized in a bright field microscope or a confocal microscope,and the optical density was obtained using MetaMorph software.

Fear Conditioning Test

On day one, animals were trained in a fear conditioning apparatus for atotal of 7 minutes with a two-pairing paradigm of cue and mild footshock (a 30-s acoustic-conditioned stimulus, 80 dB; a 2-s shockstimulus, 0.5 mA). To evaluate contextual fear learning, the animalswere returned to the training context 24 hours post-training, andfreezing behavior was scored for 5 minutes. Freezing behavior wasmonitored by MotorMonitor (Hamilton Kinder) and scored every 5 seconds.

Electrophysiology and Long-Term Potentiation (LTP) Recording

Hippocampal slices (350 mm thick) were prepared from 6-month-old PSAPPmice. Baseline responses were obtained every 10 seconds and Input-output(I/O) curves, paired-pulse modification and LTP were successivelymeasured. The stimulation intensity was set to a level that gives avalue of 30% of the maximum obtained. LTP were induced by high frequencystimulation (HFS, 100 pulses at 100 Hz, four times) or by theta-burststimulation (TBS, 10 bursts at 5 Hz, repeated 10 times in 15 sintervals).

Example 7 Dose-Dependent Activation of P₂Y₆ Receptor

Synthetic ligands were tested for activation of P₂Y₆ receptor bymeasuring receptor induced Ca²⁺ changes with the fluorescent Ca²indicator fluo-4, and results are shown in FIG. 10(A)-(K). 1321N1 humanastrocytoma cell lines either expressing P₂Y₂, P₂Y₄ or P₂Y₆ receptorswere plated into 24-well plates. Two days after plating, fluorometricmeasurements were made and responses of cells to a serial dilution ofligands were determined. P₂Y₆ mediated Ca²⁺ fluorescent change wasdetermined by normalized accumulation of fluorescent change of 3timepoints after ligand administration subtracted by value from ACSFcontrol. Changes in fluorescent intensity were plotted corresponding toligand concention in GraphPad. Dose-response curve and EC₅₀ for eachligand was estimated using nonlinear curve fit and Sigmoidaldose-response analysis. The sodium salt of compound 5 exhibited an EC₅₀of 12 nM. The sodium salt of compound 5 was demonstrated to selectivelyactivate P₂Y₆ receptors by comparing its Ca²⁺ mobilizing effects inthree 1321N1 human astrocytoma cell lines expressing P₂Y₂, P₂Y₄ or P₂Y₆receptors. The sodium salt of compound 5 was only effective at elevatingCa²⁺ levels when applied to cells expressing P₂Y₆ receptors and noteffective in P₂Y₂, or P₂Y₄ receptor expressing cells. The ability of thesodium salt of compound 5 to elevate Ca²⁺ signals in P₂Y₆ expressingcells was attenuated by addition of the P₂Y₆ antagonist MR2578. Theseexperiments demonstrated that compound 5 is a P₂Y₆ agonist.

Example 8 Acute UDP Administration Reduced Plaque Burden in PSAPP Mice

To evaluate the effect of UDP on plaque burden, two-photon microscopywas used to assess the amyloid plaques in the barrel cortex in livingPSAPP mice. Amyloid plaques were stained by systemically administeredmethoxy-X04. One day prior to imaging, PSAPP mice were injected withmethoxyX04 to label the amyloid plaques. On the imaging day, tofacilitate the re-location of the same imaging area, blood plasma waslabeled with Rhodamine dextran. Images were obtained from the samestart- and end-point to ensure the same image volume.

The results were shown in a maximum intensity projection of afluorescent stack containing 45 planes. Representative images ofmethoxyX04 labeled amyloid plaques and angiopathy on days 1 are shown inFIG. 1(A)-(C). Immediately after imaging, animals were injected withACSF or UDP intracerebroventricularly (i.c.v.) and allowed to recover.On day 4, animals were subjected to a second period of imaging of thesame regions studied on day 1 and the results are shown in FIG.1(D)-(F). The similar pattern of angiopathy (shown by open arrows)indicated the same imaging area.

Overall, decreased plaque occupied-area was observed on day 4 followingadministration of UDP. In the images with higher magnification (FIGS.1(C) and (F)), the same dense core plaques (as shown by arrows) could beidentified based on its morphology and location relative to the bloodvessel. It was observed that the dense core plaques had more intensemethoxyX04 labeling, but with decreased plaque size (as shown byarrows), when compared to the size of the same plaques on day 1. Thissuggested that acute UDP treatment reduced plaques size in live animals.This effect was further evaluated by quantifying the number of plaques,plaque load, and size of cross-section of individual plaques. See FIG.2(A)-(E). Quantitative analysis showed that acute UDP treatment led to a12.6% reduction in the number of plaques (P<0.01) and a 17.2% reductionin plaque load (P<0.01) in barrel cortex as assessed by two-photonmicroscopy. Individual identified plaques that were detected on thesecond imaging session showed an 18.2% reduction (P<0.01) incross-sectional area following UDP treatment.

After repeated imaging, brains were fixed and subjected to postmortemimmunohistochemistry with amyloid beta specific antibodies β1-40 andβ-42 to evaluate the plaque load (area occupied by immunostaining ofplaque) in cortex and hippocampus. See FIG. 3(A)-(D). UDP treatmentresulted in a 60% (p<0.05) and 62% (p<0.01) decrease in plaque load inthe cortex and hippocampus, respectively, as assessed by staining withthe β1-40 antibody. Quantification of staining with β1-42 antibodyshowed a 48% (P<0.01) and 47% (P<0.05) decrease in plaque load in thecortex and hippocampus, respectively. See FIG. 4(A)-(F). Both in vivoimaging and post hoc staining showed decrease in plaque burden in brainsof PSAPP mice, consistent with reduced plaque load in the tested animalsfollowing acute administration of UDP (e.g., a P₂Y₆ agonist).

Example 9 Activation of P₂Y₆ Receptors Reduced Plaque Burden in PSAPPMice

3-phenacyl-UDP (also referred to as PSB0474) is a potent and selectiveP₂Y₆ receptor agonist (EC50=70 nM, >500-fold selective). In this study,P₂Y₆ receptor was activated in vivo using 3-phenacyl-UDP (PSB0474). Theeffect of this activation may have on plaque burden was also evaluated.

PSB0474 was systemically administered to PSAPP mice via intraperitonealinjection for 2, 4 and 6 consecutive days. In one group, prior toevaluation and following to administration for 6 consecutive days,treatment was suspended for two weeks (6+2 weeks group). Brains werethen fixed and plaque load was evaluated by immunostaining with theamyloid beta specific antibodies: β1-40 and β1-42. Representative imagesof plaque load in cortex and hippocampus from animals that receivedinjections of PSB0474 according to the foregoing injection schedules areshown in FIG. 5(A)-(D). Quantitative data showed that administration ofPSB0474 for 4 and 6 consecutive days significantly decreasedimmunoreactivity of β1-40 in both cortex and hippocampus (FIGS. 6(A) and6(B)). Whereas, when administration of PSB0474 was stopped for 2 weeksfollowing six consecutive days of treatment (denoted as the 6+2 weeksgroup), β1-40 staining rebounded; although to a level lower thanobserved in mice treated with saline as a vehicle control. FIGS. 6A and6B depict the reduction in plaque load (%) the cortex and hippocampus,respectively, in PSAPP mice after treatment with 3-phenacyl-UDP for 2,4, or 6 consecutive days, as assayed by staining with the β1-40antibody. FIGS. 6C-6F depict data obtained following administration ofdifferent dosages of PSB0474. It is important to note that a 1000×increase in dose of PSB0474 did not cause detrimental effects to theanimal, suggesting that there is a wide therapeutic window for P2Y6receptor agonists. However, with the higher dose of 1 mg/kg we didobserve smaller effects on the efficacy endpoint presumably because theenhanced receptor occupancy led to some desensitization/internalizationof the P2Y6 receptor. This result indicates that activation of P₂Y₆significantly attenuated plaque load in both the cortex and hippocampusin PSAPP mice.

Example 10 Acute UDP Administration Improved Cognitive Function andHippocampal LTP in PSAPP Mice

Amyloid beta peptide has been reported to be toxic to synaptictransmission, and accumulation of amyloid protein is associated withcognitive impairment both in animal models of AD and in AD patients.Additionally, accumulation of amyloid protein is observed in otherconditions associated with cognitive impairment, such as in DownSyndrome. Therefore, we further investigated in PSAPP mice whether theobserved reduction in plaque burden would also lead to reversal incognitive and memory deficits typically observed in AD patients, such asimpaired cognition, impaired memory, and deficits in long-termpotentiation (LTP).

In this study, the fear conditioning associative learning paradigm wasused as a rapid cognition assay for PSAPP mice. This study allowed us toprobe cognitive function with a single training day followed in 24 hoursby tests for contextual and cued fear learning. Contextual fear learningis dependent upon a brain area that has been implicated as a locus forcognitive decline in AD: the hippocampus. Two pairings of CS-US for fearconditioning were followed 24 hours later by testing for contextual andcued fear learning. Previous studies have reported that PSAPP animalsappear to have a selective hippocampus-dependent impairment inassociative learning following two pairings of conditioned stimuli forfear conditioning.

In this study, it was found that PSAPP mice treated with ACSF showed lowfreezing behavior during 5 minute-testing time (FIG. 7(A)), which issimilar to the level reported in previous study (Dineley, et al. 2002).After UDP treatment, PSAPP mice exhibited increased freezing behaviorduring the first 4 minutes but not during the last minute. Analysis oftotal freezing percentage (FIGS. 7(B) and 7(C)) showed that PSAPP micetreated with acute UDP exhibited significantly higher freezing behavior(49%±5%) compared to an animal treated with ACSF (18%±3%). This datasuggested that acute UDP treatment rescued the deficit in contextualfear learning in PSAPP mice.

In the fear conditioning test mice exhibit a freezing behavior if theyhave a memory of the application of the aversive shock that wasdelivered 24 hours earlier. When placed in the appropriate environmentthe mice “freeze” and do not explore their environment as theyanticipate the delivery of an additional shock. Thus the greater percenttime that they exhibit freezing indicates a greater memory of theirprevious experience and thus improved memory. This represents a decreasein the cognitive impairment observed in the untreated mice.

Accumulated evidence has shown that amyloid peptides naturally secretedor isolated from Alzheimer's brains impair synaptic plasticity,especially hippocampal long-term potentiation (Walsh et al., 2002).Therefore, we further performed LTP recordings in PASPP mice andinvestigated whether P₂Y₆ receptor-mediated plaque clearance affectssynaptic plasticity. In this study, LTP was successfully induced in CA1area of the hippocampus in aged PSAPP mice with high-frequencystimulation (HFS, 100 pulses at 100 Hz, four times in 20 s intervals).First, it was observed that LTP at the schaffer collateral synapsewithin the CA1 region was depressed in PSAPP mice, as compared withlittermates (FIG. 8(A)). This result confirmed previous reports aboutsynaptic toxicity of Abeta. Acute UDP treatment reversed this LTPdeficit in PSAPP mice, and the LTP significantly increased compared withmice injected with ACSF (FIG. 8(B)). Analysis of the last 15 minpotentiation showed a significant increase in field excitatorypostsynaptic potential (fEPSP) in PSAPP mice treated with UDP, which iscomparable to the level in PSAPP littermates (FIG. 8(C)). These datasupports the conclusion that activation of P₂Y₆ rescues the LTPdeficiency in PSAPP mice, which is consistent with improvement incognition mediated by P₂Y₆ receptor.

Example 11 Activation of P₂Y₆ Receptor with Chronic Injection of PSB0474Improved Cognitive Function of PSAPP Mice

Similar to acute UDP treatment, chronic injection of the P2Y6 agonist3-phenacyl-UDP (PSB0474) increased total freezing percentage in contexttest in PSAPP mice (FIG. 9(A)-(C)). In this study, PSB0474 wasadministered at two different doses, both of which showed beneficialeffect in improving cognitive function in the PSAPP mice.

Example 12 Activation of P₂Y₆ Receptor with Compound 5 ImprovedCognitive Function of PSAPP Mice and Reduced Plaque Burden in PSAPP Mice

In this study, compound 5 was injected intraperitoneally into 6 to7-month-old PSAPP and WT mice daily at two different doses, i.e., 1ug/kg or 1 mg/kg of compound 5 (in 1% DMSO/PBS) for 7 consecutive days.Consistent with the results observed following acute UDP or PSB0474treatment, treatment with compound 5 increased total freezing percentagein the context test in PSAPP mice (FIG. 11). FIG. 11 shows freezingbehavior (freezing %) of PASPP mice in fear conditioning studies aftertreatment with vehicle control or compound 5. FIG. 11 depicts theresults of experiments using the contextual fear conditioning test withPSAPP mice treated with vehicle control (black bar at center of graph).These mice showed significantly decreased freezing percentage comparedto the age-matched wildtype animals (white bar); indicative of thememory deficits and cognitive impairment in PSAPP mice. Administrationof compound 5 prior to testing significantly improved the freezingbehavior (hatched bar at right of graph) compared to the controltreatment. In fact, this behavior which is indicative of cognitivefunction and memory was restored to a level equivalent to that observedin wildtype animals. This result is consistent with the conclusion thatcompound 5 improved cognitive function (decreased cognitive deficits) inthese mice, such as by improving memory and/or learning.

Treatment with compound 5 was also found to reduce the plaque burden incortex and hippocampus of PSAPP mice (FIG. 12 (A)-(C)). FIG. 12 showsplaque load in the cortex (Cx) and hippocampus (Hp) of the PSAPP miceafter treatment with compound 5 or vehicle control, as assayed using theamyloid beta specific antibody β1-42. FIG. 12A depicts the substantialdecrease in Aβ plaque load (%) in the cortex following treatment withcompound 5, in comparison to the vehicle control. FIG. 12 B depicts thesubstantial decrease in Aβ plaque load (%) in the hippocampus followingtreatment with compound 5, in comparison to the vehicle control. FIG.12C shows postmortem immunohistochemistry analysis of the plaque load incortex and hippocampus of PSAPP mice after treatment with compound 5 orvehicle control. Amyloid beta specific antibody β1-42 was used in theanalysis.

To generate these graphs showing plaque load, mice were euthanized,brain sections cut and antibodies directed against Aβ42 were used todisclose Aβ plaques. Images were acquired digitally and an algorithm wasapplied to threshold the image so that plaques were isolated from thebackground. The algorithm then calculated the percent area of the fieldof view occupied by the plaques.

The invention claimed is:
 1. A compound of formula I:

or a salt thereof, wherein: A is

wherein A is optionally further substituted with one or more R⁷; X isindependently selected from —O—, —S—, —N(R⁵)— and a (C1-C3)-aliphaticgroup independently and optionally substituted with one or more R⁴; Y isa bond or a (C1-C5)-aliphatic group independently and optionallysubstituted with one or more R⁴; Z and W are each independently selectedfrom ═O, ═S, ═N(R⁵), and ═NOR⁵; R¹ is selected from: —H, halogen, —OR⁵,—CN, —CF₃, —OCF₃ and a (C1-C6)-aliphatic group optionally substitutedwith one or more R⁷; R² and R³ are each independently selected from—OR⁵, —SR⁵, —NR⁵R⁶ and —OC(O)R⁵; each occurrence of R⁴ is independentlyselected from: halogen, —OR⁵, —NO₂, —CN, —CF₃, —OCF₃, —R⁵,1,2-methylenedioxy, 1,2-ethylenedioxy, —N(R⁵)₂, —SR⁵, —SOR⁵, —SO₂R⁵,—SO₂N(R⁵)₂, —SO₃R⁵, —C(O)R⁵, —C(O)C(O)R⁵, —C(O)CH₂C(O)R⁵, —C(S)R⁵,—C(S)OR⁵, —C(O)OR⁵, —C(O)C(O)OR⁵, —C(O)C(O)N(R⁵)₂, —OC(O)R⁵,—C(O)N(R⁵)₂, —OC(O)N(R⁵)₂, —C(S)N(R⁵)₂, —(CH₂)₀₋₂NHC(O)R⁵,—N(R⁵)N(R⁵)COR⁵, —N(R⁵)N(R⁵)C(O)OR⁵, —N(R⁵)N(R⁵)CON(R⁵)₂, —N(R⁵)SO₂R⁵,—N(R⁵)SO₂N(R⁵)₂, —N(R⁵)C(O)OR⁵, —N(R⁵)C(O)R⁵, —N(R⁵)C(S)R⁵,—N(R⁵)C(O)N(R⁵)₂, —N(R⁵)C(S)N(R⁵)₂, —N(COR⁵)COR⁵, —N(OR⁵)R⁵,—C(═NH)N(R⁵)₂, —C(O)N(OR⁵)R⁵, —C(═NOR⁵)R⁵, —OP(O)(OR⁵)₂, —P(O)(R⁵)₂,—P(O)(OR⁵)₂, or —P(O)(H)OR⁵); each occurrence of R⁵ is independentlyselected from: H—, (C1-C12)-aliphatic-, (C3-C10)-cycloalkyl- or-cycloalkenyl-, [(C3-C10)-cycloalkyl or-cycloalkenyl]-(C1-C12)-aliphatic-, (C6-C10)-aryl-,(C6-C10)-aryl-(C1-C12)aliphatic-, (C3-C10)-heterocyclyl-,(C6-C10)-heterocyclyl-(C1-C12)aliphatic-, (C5-C10)-heteroaryl-, and(C5-C10)-heteroaryl-(C1-C12)-aliphatic-; wherein two R⁵ groups bound tothe same atom optionally form a 3- to 10-membered aromatic ornon-aromatic ring having up to 3 heteroatoms independently selected fromN, O, S, SO, or SO₂, wherein said ring is optionally fused to a(C6-C10)aryl, (C5-C10)heteroaryl, (C3-C10)cycloalkyl, or a(C3-C10)heterocyclyl; and wherein each R⁵ group is independently andoptionally substituted with one or more R⁷; R⁶ is selected from: —R⁵,—C(O)R⁵, —C(O)OR⁵, —C(O)N(R⁵)₂ and —S(O)₂R⁵; each occurrence of R⁷ isindependently selected from: halogen, —OR⁸, —NO₂, —CN, —CF₃, —OCF₃, —R⁸,oxo, thioxo, 1,2-methylenedioxy, 1,2-ethylenedioxy, —N(R⁸)₂, —SR⁸,—SOR⁸, —SO₂R⁸, —SO₂N(R⁸)₂, —SO₃R⁸, —C(O)R⁸, —C(O)C(O)R⁸, —C(O)CH₂C(O)R⁸,—C(S)R⁸, —C(S)OR⁸, —C(O)OR⁸, —C(O)C(O)OR⁸, —C(O)C(O)N(R⁸)₂, —OC(O)R⁸,—C(O)N(R⁸)₂, —OC(O)N(R⁸)₂, —C(S)N(R⁸)₂, —(CH₂)₀₋₂NHC(O)R⁸,—N(R⁸)N(R⁸)COR⁸, —N(R⁸)N(R⁸)C(O)OR⁸, —N(R⁸)N(R⁸)CON(R⁸)₂, —N(R⁸)SO₂R⁸,—N(R⁸)SO₂N(R⁸)₂, —N(R⁸)C(O)OR⁸, —N(R⁸)C(O)R⁸, —N(R⁸)C(S)R⁸,—N(R⁸)C(O)N(R⁸)₂, —N(R⁸)C(S)N(R⁸)₂, —N(COR⁸)COR⁸, —N(OR⁸)R⁸,—C(═NH)N(R⁸)₂, —C(O)N(OR⁸)R⁸, —C(═NOR⁸)R⁸, —OP(O)(OR⁸)₂, —P(O)(R⁸)₂,—P(O)(OR⁸)₂, or —P(O)(H)(OR⁸); and each occurrence of R⁸ isindependently selected from: H— and (C1-C6)-aliphatic-.
 2. The compoundof claim 1, wherein X is —O—.
 3. The compound of claim 1, wherein R¹ is—H, bromine, iodine, methyl, ethyl or —CF₃.
 4. The compound of claim 3,wherein R¹ is —H.
 5. The compound of claim 1, wherein Z is ═O or ═S. 6.The compound of claim 5, wherein Z is ═O.
 7. The compound of claim 1,wherein W is ═O or ═S.
 8. The compound of claim 7, wherein W is ═O. 9.The compound of claim 1, wherein Y is a C1-aliphatic group optionallysubstituted with one or more R⁴.
 10. The compound of claim 9, wherein Yis —CH₂—.
 11. The compound of claim 1, wherein Y is a C2-aliphatic groupoptionally substituted with one or more R⁴.
 12. The compound of claim11, wherein Y is —CH₂—C(R⁴)₂—.
 13. The compound of claim 12, wherein Yis —CH₂—CH₂—.
 14. The compound of claim 13, wherein each occurrence ofR⁴ is independently selected from halogen.
 15. The compound of claim 14,wherein both occurrences of R⁴ are —F.
 16. The compound of claim 12,wherein each occurrence of R⁴ is independently a (C1-C3)-aliphaticgroup.
 17. The compound of claim 16, wherein both occurrences of R⁴ are—CH₃.
 18. The compound of claim 1, wherein R² is —OR⁵.
 19. The compoundof claim 18, wherein R² is —OH.
 20. The compound of claim 1, wherein R³is —OR⁵.
 21. The compound of claim 20, wherein R³ is —OH.
 22. A compoundof formula II:

or a salt thereof, wherein: A is an aromatic group selected from:

wherein A is optionally further substituted with one or more R⁴; X isindependently selected from —O—, —S—, —N(R⁵)— and a (C1-C3)-aliphaticgroup independently and optionally substituted with one or more R⁴; Y¹is a (C1-C5)-aliphatic group substituted with at least one oxo andfurther independently and optionally substituted with one or more R⁴; Zand W are each independently selected from ═O, ═S, ═N(R⁵), and ═NOR⁵; R¹is selected from: —H, halogen, —OR⁵, —CN, —CF₃, —OCF₃ and a(C1-C6)-aliphatic group optionally substituted with one or more R⁴; R²and R³ are each independently selected from —OR⁵, —SR⁵, —NR⁵R⁶ and—OC(O)R⁵; each occurrence of R⁴ is independently selected from: halogen,—OR⁵, —NO₂, —CN, —CF₃, —OCF₃, —R⁵, oxo, thioxo, 1,2-methylenedioxy,1,2-ethylenedioxy, —N(R⁵)₂, —SR⁵, —SOR⁵, —SO₂R⁵, —SO₀₂N(R⁵)₂, —SO₃R⁵,—C(O)R⁵, —C(O)C(O)R⁵, —C(O)CH₂C(O)R⁵, —C(S)R⁵, —C(S)OR⁵, —C(O)OR⁵,—C(O)C(O)OR⁵, —C(O)C(O)N(R⁵)₂, —OC(O)R⁵, —C(O)N(R⁵)₂, —OC(O)N(R⁵)₂,—C(S)N(R⁵)₂, —(CH₂)_(—) ₂NHC(O)R⁵, —N(R⁵)N(R⁵)COR⁵, —N(R⁵)N(R⁵)C(O)OR⁵,—N(R⁵)N(R⁵)CON(R⁵)₂, —N(R⁵)SO₂R⁵, —N(R⁵)SO₂N(R⁵)₂, —N(R⁵)C(O)OR⁵,—N(R⁵)C(O)R⁵, —N(R⁵)C(S)R⁵, —N(R⁵)C(O)N(R⁵)₂, —N(R⁵)C(S)N(R⁵)₂,—N(COR⁵)COR⁵, —N(OR⁵)R⁵, —C(═NH)N(R⁵)₂, —C(O)N(OR⁵)R⁵, —C(═NOR⁵)R⁵,—OP(O)(OR⁵)₂, —P(O)(R⁵)₂, —P(O)(OR⁵)₂, or —P(O)(H)(OR⁵); each occurrenceof R⁵ is independently selected from: H—, (C1-C12)-aliphatic-,(C3-C10)-cycloalkyl- or -cycloalkenyl-, [(C3-C10)-cycloalkyl or-cycloalkenyl]-(C1-C12)-aliphatic-, (C6-C10)-aryl-,(C6-C10)-aryl-(C1-C12)aliphatic-, (C3-C10)-heterocyclyl-,(C6-C10)-heterocyclyl-(C1-C12)aliphatic-, (C5-C10)-heteroaryl-, and(C5-C10)-heteroaryl-(C1-C12)-aliphatic-; wherein two R⁵ groups bound tothe same atom optionally form a 3- to 10-membered aromatic ornon-aromatic ring having up to 3 heteroatoms independently selected fromN, O, S, SO, or SO₂, wherein said ring is optionally fused to a(C6-C10)aryl, (C5-C10)heteroaryl, (C3-C1-10)cycloalkyl, or a(C3-C10)heterocyclyl; and wherein each R⁵ group is independently andoptionally substituted with one or more R⁷; R⁶ is selected from: —R⁵,—C(O)R⁵, —C(O)OR⁵, —C(O)N(R⁵)₂ and —S(O)₂R⁵; each occurrence of R⁷ isindependently selected from: halogen, —OR⁸, —NO₂, —CN, —CF₃, —OCF₃, —R⁸,oxo, thioxo, 1,2-methylenedioxy, 1,2-ethylenedioxy, —N(R⁸)₂, —SR⁸,—SOR⁸, —SO₂R⁸, —SO₂N(R⁸)₂, —SO₃R⁸, —C(O)R⁸, —C(O)C(O)R⁸, —C(O)CH₂C(O)R⁸,—C(S)R⁸, —C(S)OR⁸, —C(O)OR⁸, —C(O)C(O)OR⁸, —C(O)C(O)N(R⁸)₂, —OC(O)R⁸,—C(O)N(R⁸)₂, —OC(O)N(R⁸)₂, —C(S)N(R⁸)₂, —(CH₂)₀₋₂NHC(O)R⁸,—N(R⁸)N(R⁸)COR⁸, —N(R⁸)N(R⁸)C(O)OR⁸, —N(R⁸)N(R⁸)CON(R⁸)₂, —N(R⁸)SO₂R⁸,—N(R⁸)SO₂N(R⁸)₂, —N(R⁸)C(O)OR⁸, —N(R⁸)C(O)R⁸, —N(R⁸)C(S)R⁸,—N(R⁸)C(O)N(R⁸)₂, —N(R⁸)C(S)N(R⁸)₂, —N(COR⁸)COR⁸, —N(OR)R⁸,—C(═NH)N(R⁸)₂, —C(O)N(OR⁸)R⁸, —C(═NOR⁸)R⁸, —OP(O)(OR⁸)₂, —P(O)(R⁸)₂,—P(O)(OR⁸)₂, or —P(O)(H)(OR⁸); and each occurrence of R⁸ isindependently selected from: H— and (C1-C6)-aliphatic-.
 23. The compoundof claim 1, wherein the compound is selected from:

or a pharmaceutically acceptable salt thereof.
 24. The compound of claim1, wherein the compound is

or a pharmaceutically acceptable salt thereof.
 25. A pharmaceuticalcomposition, comprising a compound according to claim 1 and anacceptable carrier, adjuvant or vehicle.
 26. A method for treating adisorder in a subject in need thereof, comprising administering atherapeutically effective amount of a compound according to claim 1,wherein said disorder is selected from a neurodegenerative disorder, atraumatic brain injury and pain.
 27. The method of claim 26, wherein thedisorder is a neurodegenerative disorder.
 28. The method of claim 27,wherein the neurodegenerative disorder is Alzheimer's disease.
 29. Themethod of claim 27, wherein the neurodegenerative disorder isParkinson's disease.
 30. The method of claim 26, wherein the disorder isa traumatic brain injury or pain.
 31. A pharmaceutical compositioncomprising a compound according to claim 23 and an acceptable carrier,adjuvant or vehicle.
 32. A pharmaceutical composition comprising acompound according to claim 24 and an acceptable carrier, adjuvant orvehicle.
 33. A method for treating a disorder in a subject in needthereof, comprising administering a therapeutically effective amount ofa compound according to claim 24, wherein said disorder is selected froma neurodegenerative disorder, a traumatic brain injury and pain.
 34. Themethod of claim 33, wherein the disorder is a neurodegenerativedisorder.
 35. The method of claim 34, wherein the neurodegenerativedisorder is Alzheimer's disease.
 36. The method of claim 34, wherein theneurodegenerative disorder is Parkinson's disease.
 37. The method ofclaim 33, wherein the disorder is a traumatic brain injury or pain. 38.A pharmaceutical composition, comprising a compound according to claim22, and an acceptable carrier, adjuvant or vehicle.
 39. The compound ofclaim 22, wherein X is —O—.
 40. The compound of claim 22, wherein R¹ is—H, bromine, iodine, methyl, ethyl or —CF_(3.)
 41. The compound of claim40, wherein R¹ is —H.
 42. The compound of claim 22, wherein Z is =O or=S.
 43. The compound of claim 42, wherein Z is =O.
 44. The compound ofclaim 22, wherein W is =O or =S.
 45. The compound of claim 44, wherein Wis =O.
 46. The compound of claim 22, wherein R² is —OR^(5.)
 47. Thecompound of claim 46, wherein R² is —OH.
 48. The compound of claim 22,wherein R³ is —OR^(5.)
 49. The compound of claim 48, wherein R³ is —OH.50. The compound of claim 22, wherein Y¹ is a Cl-aliphatic groupsubstituted with oxo.
 51. The compound of claim 22, wherein Y¹ is aC2-aliphatic group substituted with at least one oxo and optionallysubstituted with one or more R^(4.)
 52. The compound of claim 51,wherein Y¹ is —CO—C(R⁴)₂— or —C(R⁴)₂—CO—.
 53. The compound of claim 52,wherein Y¹ is —CO—CH₂— or —CH₂—CO—.
 54. The compound of claim 52,wherein each occurrence of R⁴ in Y¹ is independently selected fromhalogen.
 55. The compound of claim 54, wherein both occurrences of R⁴are —F.
 56. The compound of claim 52, wherein each occurrence of R⁴ inY¹ is independently a (C1-C3)-aliphatic group.
 57. The compound of claim56, wherein both occurrences of R⁴ are —CH_(3.)